A blueprint
for dementia
research
A blueprint
for dementia
research
A blueprint for dementia research
ISBN 978-92-4-005824-8 (electronic version)
ISBN 978-92-4-005825-5 (print version)
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Contents
Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii
1.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1 Rationale for this blueprint. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2 Objectives of this blueprint. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3 About this blueprint.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
2
3
2.
Drivers of dementia research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1 Empowerment and engagement of people with lived experience. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2 Diversity and equity.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.3 Funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.4 Access to science, data and materials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.5 Capacity-building for research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.6 Technology.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.7 Knowledge translation and exchange.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.8 Regulatory environment.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.
Dementia epidemiology and economics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1 Context. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Research gaps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3 Strategic goals, actions and milestones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.
Dementia disease mechanisms and models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4.1 Context. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4.2 Research gaps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4.3 Strategic goals, actions and milestones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.
Diagnosis of dementia.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.1 Context. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.2 Research gaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.3 Strategic goals, actions and milestones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.
Drug development and clinical trials for dementia.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1 Context. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2 Research gaps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3 Strategic goals, actions and milestones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
15
16
18
34
34
35
36
iii
7.
Dementia care and support.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
7.1 Context. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
7.2 Research gaps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
7.3 Strategic goals, actions and milestones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.
Dementia risk reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1 Context. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2 Research gaps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3 Strategic goals, actions and milestones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.
Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
45
45
46
48
References.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Annex: Summary of research themes, strategic goals and milestones.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
iv
A blueprint for dementia research
Foreword
Addressing dementia is one of the greatest health challenges of our generation.
In the years ahead, societies and health systems will have to cope with a staggering increase in the number
of people with dementia, which is set to reach 78 million by the end of this decade, with most of these people
living in low- and-middle-income countries.
Now, more than ever, we need to work together as a global community, leveraging the unique knowledge and
expertise that each of us has to offer. During the COVID-19 pandemic, we have learned how fast we can advance
research and development if we act in a coordinated manner. It is now time to translate these learnings to
address another global health challenge that we’ve been confronted with for years: dementia. It is therefore
timely for WHO to publish this blueprint for dementia research, the first WHO initiative of this kind in the context
of non-infectious diseases.
This blueprint builds on and applies key lessons learned from previous WHO efforts to prioritize and coordinate
research for infectious diseases, and considers the entire dementia research spectrum, incorporating diagnostics
and therapeutics, as well as emerging scientific and technological advances such as artificial intelligence,
multiomics, and biomarkers. It also encompasses epidemiology, health economics, care and carer research, risk
reduction, and brain health across the life course. The blueprint emphasizes that advances in these areas will
only be fully accomplished if appropriate and sustainable funding is allocated, diversity and equity become the
norm, and people with lived experience are included throughout the entire research process.
Achieving these goals means reaching beyond our traditional ways of doing research and finding better
strategies to coordinate between sectors and stakeholders. As a key component to support the implementation
of the global action plan on the public health response to dementia 2017–2025, the blueprint for dementia
research identifies knowledge gaps and defines actions and milestones to achieve strategic research goals. This
blueprint is designed to provide guidance to policy makers, funders, and the research community on dementia
research, making it more efficient, equitable, and impactful.
We must come together globally, and in a coordinated manner, to tackle dementia and halt the debilitating
impact it has on people and communities.
Dr Soumya Swaminathan
Chief Scientist
World Health Organization
Dr Ren Minghui
Assistant Director General
UHC/Communicable &
Noncommunicable Diseases
World Health Organization
v
Acknowledgements
The blueprint for dementia research was conceptualised by Tarun Dua, Dévora Kestel and Soumya Swaminathan.
The overall blueprint development was led by Neerja Chowdhary, Rodrigo Cataldi, Katrin Seeher and Vasee
Moorthy.
The blueprint was drafted by the following collaborators from the Centre of Healthy Brain Ageing,
University of New South Wales and University of Sydney, Sydney, Australia: Perminder S. Sachdev; Adam
Bentvelzen; Nady Braidy; Henry Brodaty; Nicole Kochan; Ben Lam; Darren Lipnicki; Lee-Fay Low; Karen Mather;
Louise Mewton; Katya Numbers; Anne Poljak; Suraj Samtani; Wei Wen.
The following experts and people with lived experience have participated in the survey, consultation
and/or reviewed the blueprint: Emiliano Albanese (Università della Svizzera Italiana, Switzerland); Ricardo
Allegri (Instituto de Investigaciones Neurológicas Fleni, Argentina); Philippe Amouyel (University Hospital of
Lille, France); Katrin Amunts (University Hospital Düsseldorf, Germany); Tuan Anh Nguyen (National Ageing
Research Institute, Australia); Kaarin Anstey (University of New South Wales, Australia); John Ataguba (University
of Manitoba, Canada); Paola Barbarino (Alzheimer’s Disease International, United Kingdom of Great Britain
and Northern Ireland (United Kingdom)); Angela Bradshaw (Alzheimer Europe, Luxembourg); Carol Brayne
(University of Cambridge, United Kingdom); Paulo Caramelli (Faculdade de Medicina, Universidade Federal de
Minas Gerais, Brazil); Maria Carrillo (Alzheimer’s Association, United States of America (USA)); Lindsey Caldwell
(UK Dementia Research Institute, United Kingdom); James Cole (University College London, United Kingdom);
Adelina Comas Herrera (London School of Economics and Political Science, United Kingdom), Anna Maria de
Benedetti (Repubblica e Cantone Ticino, Switzerland), Bart De Strooper (UK Dementia Research Institute,
United Kingdom); Maria Teresa Ferretti (Women’s Brain Project, Switzerland); Franca Gatto (Public Health
Agency of Canada, Canada); Serge Gauthier (McGill University, Canada); Jean Georges (Alzheimer Europe,
Luxembourg); Riadh Gouidier (Razi Hospital La Manouba, Tunisia); Ishtar Govia (The University of the West
Indies, Jamaica); Anders Gustavsson (Karolinska Institutet, Sweden); Oskar Hansson (Lund University, Sweden);
Berrie Holtzhausen (Alzheimer Dementia Namibia, Namibia); Jacqueline Hoogendam (Ministry of Health, Welfare
and Sport, Netherlands); Yun-Hee Jeon (University of Sydney, Australia); Hussain Jafri (Alzheimer’s Pakistan,
Pakistan); Yves Joanette (Université de Montreal/CRIUGM, Canada); Hanadi Khamis Al Hamad (Qatar University,
Qatar); Jiban Kanai Das (Sir William Beveridge Foundation, Bangladesh); Miia Kivipelto (Karolinska Institutet,
Sweden); Martin Knapp (London School of Economics, United Kingdom); Susan Kohlhaas (Alzheimer Research
UK, United Kingdom); Zoe Kourtzi (University of Cambridge, United Kingdom); Giovanna Lalli (UK Dementia
Research Institute, United Kingdom); Raj Long (Independent Development, Regulatory and Access Expert, United
Kingdom); Benedetta Mannini (University of Cambridge, United Kingdom); Roger Marple (Living with Alzheimer’s
and Dementia advocate, Canada); Ruth McKernan (Dementia Discovery Fund, United Kingdom); Nagaendran
Kandiah (Duke-NUS, Singapore); David Ndetei (Africa Mental Health Research and Training Foundation, Kenya);
Pierluigi Nicotera (German Centre for Neurodegenerative Diseases); Meera Pattabiraman (Alzheimer’s and
Related Disorders Society of India, India); Cleusa Ferri (Universidade Federal de São Paulo, Brazil); Mario Possenti
(Alzheimer Society, Italy); Vijayalakshmi Ravindranath (Indian Institute of Science, India); Louise Robinson
(Newcastle University, United Kingdom); Martin Rossor (University College London, United Kingdom); Jane
Rylett (Canadian Institutes of Health Research, Canada); Mohamed Sakel (Sir William Beveridge Foundation,
Bangladesh); Manab Sarker (Sir William Beveridge Foundation, Bangladesh); Andrew Saykin (Indiana University
School of Medicine, USA); Susan Schwarz (Global Coalition on Aging, USA); Gerard Schellenberg (University of
Pennsylvania, USA); Lenny Shallcross (World Dementia Council, United Kingdom); Sarah Smith (Leeds Beckett
University, United Kingdom); Saskia Sivananthan (Alzheimer’s Society Canada, Canada); Claire Surr (Leeds
Beckett University, United Kingdom); Rudolph Tanzi (Harvard University, USA); David Thomas (Alzheimer’s
vi
Research UK, United Kingdom); David Truswell (Dementia Alliance for Culture and Ethnicity, United Kingdom);
Lindsay Wallace (University of Cambridge, United Kingdom), Huali Wang (Peking University Institute of Mental
Health, China); Tan Weng Mooi (Ministry of Health Office for Healthcare Transformation, Singapore); Anders
Wimo (Karolinska Institutet, Sweden).
Valuable technical inputs were received from the following WHO colleagues at headquarters and in
regional offices: Taghreed Adam (Science Division); Florence Baingana (Regional Officer for Africa); Anshu
Banerjee (Maternal, Newborn, Child and Adolescent Health & Ageing); Elaine Brohan (Brain Health); Andrea
Bruni (Regional Office for South-East Asia); Vanessa Cavallera (Brain Health); Jorge Castro (Brain Health);
Matteo Cesari (Ageing and Health); Daniel Chisholm (Mental Health and Substance Use); Alarcos Cieza (Sensory
Functions, Disability and Rehabilitation); Chencho Dorji (Regional Office for South-East Asia); Batool Fatima (Brain
Health); Stéfanie Fréel (Brain Health); Michelle Funk (Policy, Law and Human Rights); Laura Garcia Diaz (Brain
Health); Kavitha Kolappa (Brain Health); Ledia Lazeri (Regional Officer for Europe); Gergana Manolova (Brain
Health); Alana Officer (Demographic Change and Healthy Ageing); Renato Oliveira e Souza (Regional Office for
the Americas); Mark van Ommeren (Mental Health); Vladimir Poznyak (Alcohol, Drugs and Addictive Behaviours);
Alexandra Rauch (Sensory Functions, Disability and Rehabilitation); Ritu Sadana (Ageing and Health); Khalid
Saeed (Regional Office for the Eastern Mediterranean); Yuka Sumi (Ageing and Health); Nicoline Schiess (Brain
Health); Chiara Servili (Brain Health); Jessica Spagnolo (Brain Health); Jotheeswaran Thiyagarajan (Ageing and
Health); Martin Vandendyck (Regional Office for the Western Pacific).
Financial support for this publication was provided by Gates Ventures.
Acknowledgements
vii
Abbreviations
viii
AD
Alzheimer disease
CT
Computed tomography
DALYs
Disability-adjusted life-years
DLB
Dementia with Lewy bodies
GBD
Global Burden of Diseases Study
HIC
High-income countries
LMIC
Low- and middle-income countries
MCI
Mild cognitive impairment
MRI
Magnetic resonance imaging
NCDs
Noncommunicable diseases
PET
Positron emission tomography
PPC
Preferred product characteristics
SCD
Subjective cognitive decline
TPP
Target product profile
TDP-43
TAR DNA-binding protein-43
VaD
Vascular dementia
1. Introduction
1.1 Rationale for this
blueprint
Dementia is a major cause of disability and dependence
in older adults worldwide. It affects memory and
other cognitive functions, leads to changes in mood
and behaviours, and interferes with the ability to
perform daily activities and participate independently
in society. Dementia causes significant burden on
individuals and their families as well as on health,
social welfare, and financial systems in all countries.
Approximately 55.2 million people have dementia
worldwide, over 60% of whom live in low- and middleincome countries (LMIC) (1, 2). With life expectancy
increasing in almost every country and older age being
the strongest independent risk factor for dementia,
the number of people living with dementia is expected
to rise to 78 million by 2030 (2) (Fig. 1). In 2019,
dementia was the seventh leading cause of death
worldwide, accounting for 1.6 million deaths (Fig.
1), and 28.3 million disability-adjusted life-years (1).
The global cost of medical, social, and informal care
associated with dementia in 2019 was estimated to be
more than US$ 1.3 trillion and this cost is expected to
exceed US$ 2.8 trillion by 2030 (1).
Despite the recognition that dementia research
should be accelerated, it remains fragmented, with
wide variation in the types and levels of investment,
as well as research quality. Moreover, research into
dementia risk factors and effective interventions
to reduce risk must be carried out over long time
periods as dementia risk accumulates over the life
Fig. 1. Worldwide impact of dementia in 2019
7th leading cause of death
1.6 million deaths in 2019
188% increase since 2000
139 M
78 M
55 M
2019
2030
2050
High-income countries
Lower-middle-income countries
Upper-middle-income countries
Low-income countries
Source: Global status report on the public health response to dementia (1).
1
course and the lag time between exposure to risks
and/or interventions and the onset of dementia may
be very long. Similarly, research into novel therapies
tends to have lower success rates, take longer to
conduct, and face difficulties in patient recruitment (3).
Consequently, market incentives, public investment,
and research outputs remain lower than for other
disorders (4). Research on dementia is also inequitable,
as the vast majority of studies are conducted in highincome countries (HIC), despite most people with
dementia living in LMIC. Data for 2019 indicate that,
although funding for dementia has increased, it is
primarily directed towards research in HIC. Of the
50 organizations and institutions that received the
most grants for dementia research in 2019, 41 were
in the USA, six in the United Kingdom, and three
in Canada (1). Additionally, despite dementia being
caused by several diseases, most research is on
Alzheimer disease (AD). Therefore, global dementia
research must be strengthened to include other
underlying causes of dementia, all potential risk and
protective factors, as well as care and support for
those living with dementia and their carers. Moreover,
while the global scale of the dementia challenge needs
to be reflected in research efforts, regional differences
and the heterogeneity of populations deserve much
more attention.
During the G8 dementia summit in 2013, countries
collectively pledged to enhance coordination for
more innovation in therapeutic approaches, and to
increase structured funding for dementia research
by setting the ambitious goal of identifying a cure
or disease-modifying therapy by 2025. Similarly, in
2017, all 194 WHO Member States adopted the global
action plan on the public health response to dementia
2017–2025 (4) and committed to strengthening
their response to dementia, supporting people with
dementia and their families, as well as achieving the
targets set in the action plan by 2025. Commitment
to the global dementia action plan was reinforced by
the G20 countries in 2019, as they recognized the
impact of dementia and urged countries to develop
ambitious national responses and adopt integrated
approaches aligned with the global dementia action
plan. Notwithstanding such commitments, the
targets set by the global dementia action plan are
unlikely to be reached by 2025 (1). Similarly, the lack of
progress in all dementia action areas compromises the
efforts towards achieving other global commitments
including the Sustainable Development Goals targets,
2
A blueprint for dementia research
such as universal health coverage, and the action
areas of the United Nations Decade of Healthy Ageing.
In the face of this challenge, urgent action is
needed in making research an integral part of the
response to dementia. To ensure that all aspects of
research (including basic science, clinical research
and implementation science) as well as critical
areas across the dementia care pathway (ranging
from risk reduction, diagnosis, treatment, care,
and rehabilitation to ultimately finding a cure) are
adequately addressed, dementia research must be
recognized as a global priority. At the same time,
investigative approaches need to be harmonized
and redundancies reduced. Moreover, research must
be rooted in equity, diversity and inclusiveness, be
person-centred, include families and reflect the reality
of dementia in different contexts. This will require
strengthening research capacity in low-income
settings and developing mechanisms to ensure the
inclusion of people from diverse cultural and ethnic
backgrounds, as well as of people living with dementia,
their families, and carers in research.
1.2 Objectives of this
blueprint
Building on previous efforts to prioritize and coordinate
research for infectious diseases, WHO set out to
develop a blueprint for dementia research (hereafter
referred to as “blueprint”) in 2021. This blueprint is
the first of its kind in the context of non-infectious
diseases and aims to support the global prioritisation
of dementia research and provide a coordination
mechanism among stakeholders.
The specific objectives of this blueprint are to:
facilitate timely and high-quality evidence
generation to address research gaps
fast-track innovation and increase intervention
success-rates
enhance and encourage collaboration in dementia
research
build research capacity, especially in LMIC
guide actions for mobilizing adequate resources
promote the empowerment and engagement of
people with lived experience and
ensure the successful and timely implementation
of research evidence.
Through these objectives, the blueprint directly
supports the implementation of the global action plan
and accelerates efforts to achieve targets that will
make research more equitable, efficient and impactful,
ultimately contributing to the provision of better care
and support for people living with dementia, their
families, and carers.
1.3 About this blueprint
Development
The blueprint was informed by a comprehensive
literature review, a survey of experts, and a
consultation workshop with international dementia
experts (i.e., researchers, academics, people living
with dementia, representatives of civil society
organizations and policy-makers). Overall, more than
100 dementia experts from around the world and
colleagues from relevant WHO departments and units
were involved in the development and peer-review
of the blueprint. Declaration of interest forms were
obtained from all external contributors prior to their
involvement in the blueprint development and any
conflicts were managed as per WHO policy.
Content
The blueprint summarizes the current state of
dementia research across six broad research themes,
identifies existing research gaps, and outlines 15
strategic goals with actions and timebound milestones
to address those gaps. The six research themes
consider the entire dementia research spectrum,
incorporating diagnostics and therapeutics, as well as
emerging scientific and technological advances such
as artificial intelligence, multiomics, and biomarkers
to increase our understanding of underlying disease
mechanisms and to foster early diagnosis and
treatment. It also encompasses epidemiology, health
economics, care and carer research, risk reduction,
and brain health across the life course.
Addressing these complex issues and existing gaps
will require an enabling research environment. The
blueprint therefore outlines eight drivers of research
that are considered to be essential in accelerating
dementia research across the six identified themes. For
instance, the strategic goals can only be accomplished
if appropriate and sustainable funding is allocated and
research capacity is built, especially in LMIC. More
emphasis needs to be put on promoting diversity and
equity in dementia research and including people
with lived experience throughout the entire research
process. The blueprint also highlights that research
progress will be driven by better coordination and
increased collaboration among research sectors,
including data-sharing to ensure better use of data,
avoid redundancy, and promote a more inclusive
research environment. Finally, encouraging the use of
new technologies will be also vital to drive innovation
in the field.
Target audience and implementation
The primary target audience for this blueprint
are national and international research agencies,
funding bodies (including governmental, private,
and philanthropic organizations), regulation
authorities, civil society, and the broader research
community working on dementia and related areas.
These stakeholder groups are encouraged to work
collaborative to address current challenges and create
a structured plan of action to promote scientific
advances in all the necessary research areas to ease
the impact of dementia everywhere.
WHO will work side by side with all stakeholders
to ensure research prioritization for dementia, the
promotion of research across all identified areas
and capacity building in all countries. This blueprint
represents a first step towards supporting these
efforts by encouraging more evenly distributed
research and innovation in both HIC and LMIC to
address regional gaps and challenges.
1. Introduction
3
Fig. 2
Objectives of the blueprint for
dementia research
Timely and high-quality evidence
Fast track innovation
Enhanced collaboration
Increased research capacity
Adequate resources
Engagement of people with lived experience
Successful and timely implementation of research
Research themes
Summarizing current state and research gaps
Dementia
epidemiology
and economics
Dementia
disease
mechanisms
and models
Dementia
diagnosis
Drug
development
and clinical trials
for dementia
Dementia care
and support
Dementia risk
reduction
15 strategic goals
Actions and timebound milestones address
research gaps
4
1
High-quality epidemiological data
9
Improving clinical trials
2
Economic impact of dementia
10
Legislative and regulatory environments
3
Understanding underlying diseases
11
Tools and methodologies for interventions
4
Models of diseases
12
Models across the continuum of care
5
Development of biomarkers
13
Methodologies and approaches for risk
reduction research
6
Development of clinical assessment of
cognition and function
14
Understanding risk factors
7
Diagnosis during prodromal stages
15
Risk reduction interventions
8
Development of novel therapies
A blueprint for dementia research
Drivers of dementia research
Empowerment and
engagement of people
with lived experience
Diversity and
equity
Funding
Access to science,
data and material
Capacity building
for research
Technology
Knowledge
translation and
exchange
Regulatory
environments
lmplementing the
blueprint
Successfully implementing the blueprint requires
empowering and engaging people with lived experience
in all aspects of research. WHO encourages national and
international research agencies, together with other
funding bodies, to use this blueprint to inform upcoming
funding streams and operationalize the outlined drivers
of research. Civil society can ensure that advocacy efforts
are likewise aligned, supporting the drive for a more
equitable, efficient, and collaborative research landscape.
Researchers can support the achievement of milestones
and strategic goals of this blueprint by addressing the
research gaps identified.
1. Introduction
5
© anyaivanova
2. Drivers of dementia
research
The blueprint is a global coordination mechanism for
transformative change, fast-tracking of innovation
and addressing long-standing barriers in dementia
research. To achieve this vision, research must take
place within an enabling environment. The eight
drivers of dementia research (Fig. 3) identified in this
chapter are considered essential to create such an
environment and support the realization of significant
progress in the field.
Fig. 3. Drivers of research on dementia
Regulatory
environment
Knowledge
translation and
exchange
Empowerment
and engagement
of people with
lived experience
Drivers of
dementia
research
Diversity
and equity
Funding
Access to science,
data and
materials
Technology
Capacity building
for research
7
2.1 Empowerment and engagement of people
with lived experience
People with lived experience of dementia (including those living
with dementia, their families and communities and formal and
informal carers) have the greatest direct interest in the outcomes
of research. It is therefore essential that they remain central to
and are directly involved in all aspects of dementia research. This
is not the norm in many parts of the world, and its introduction
will require a major shift in perspectives and approaches.
People with lived experience should be involved in all stages
of research, including setting priorities, devising procedures,
selecting outcome measures, implementing the research
strategy, disseminating results and turning recommendations
into practice and policy. The objectives of including them are to
ensure that research is directly relevant to their needs, designed
to maximize real-world benefits and minimize or eliminate harm
and is fully consistent with the United Nations Convention on the
Rights of Persons with Disabilities and other international and
regional human rights instruments. For example, the ethical and
psychological implications of disclosing the results of cognitive
tests, information on biomarkers and genetic risk profiles are not
well understood and should be a priority for further investigation,
with the involvement of people with lived experience.
People with lived experience should also be involved in committees
that oversee dementia research and be on the boards of public and
private agencies that award research funds.
Their involvement in research should take into consideration their
diversity. Many will not have a background in science or skills in
research methods. Many will have cognitive, sensory and/or physical
impairments that may affect their ability to engage, so that research
teams will have to adopt inclusive approaches to engagement.
Research training courses could enable people with lived experience
to contribute effectively to research, and researchers could provide
opportunities for people with lived experience with whom they
work. It is also important to engage people who may not have
dementia but are interested in being actively involved, for example
to reduce their risk of developing dementia. Direct involvement of
people with lived experience will ultimately benefit research, as it
is likely to encourage greater participation.
2.2 Diversity and equity
The principles of equity and diversity in, e.g., gender, race,
ethnicity, gender identity, sexual orientation, religion, disability,
socioeconomic status, marginalization and Indigenous status
must be upheld in all aspects of dementia research. This includes
equal participation, outcomes, benefits, resources, funding and
coverage. Some populations and communities are less willing or
able to participate in dementia research; therefore, the research
community and sectors should seek to understand the reasons
by engaging with them and designing research and associated
processes that make participation more feasible and acceptable.
Better understanding of the prevalence and incidence of dementia,
the costs of illness and the prevalence and impact of risk factors is
required in LMIC and other ethnic and regional groups. Research
into the mechanisms of dementia, such as biomarkers, genetic and
8
A blueprint for dementia research
epigenetic markers, should include and account for differences in
these groups.
Equity must also be assured for researchers working in underrepresented countries and regions, such as their inclusion in
decision-making, ownership and fair recognition and reward for
research outcomes.
Sex and gender equity must also be considered in all components
of dementia research. Efforts should be made to correct the
substantial underrepresentation of women in research studies
and leadership positions, with creation of research environments
that offer a fair career–life balance for women.
2.3 Funding
Even in HIC, dementia research has been chronically underfunded,
despite the high health and social burden associated with
dementia. Increasing dementia research funding, in absolute
terms and relative to that for other comparably impactful
diseases, is essential. Given the chronic, slowly progressive
nature of most diseases causing dementia, continuous funding
must be assured for comprehensive, longitudinal research, which
is often costly. Secure long-term funding is necessary for all
areas of dementia research but especially for research into novel
treatments and risk reduction. After three decades and several
hundred failed trials, many large pharmaceutical companies
have abandoned efforts around dementia therapeutics (6), as the
cost of bringing a new drug to market approval is prohibitively
high, one estimate in 2013 being about US$ 2.6 billion (7).
Nonetheless, the potential societal and economic benefits of
a successful treatment would be enormous. There is renewed
interest in the field, in part due to a collaborative approach
among industry, academia and government and also greater
attention to drug repositioning and repurposing as possible
alternative, more cost–effective treatments. Public investment
could reduce private risk and thereby reinvigorate research
and development. Work on therapeutics should therefore be
renewed, facilitated by public–private partnerships.
More funding is also necessary for research on prevention,
diagnosis, treatment (including non-pharmacological treatments)
and for high-quality care. Clinical translation and implementation
should also be studied further and appropriately funded.
Increased funding for dementia research should be provided by
public, private and philanthropic funding organizations. Funding
should be better balanced, including for under-researched
aspects of dementia, such as conditions other than AD and
dementia in highly vulnerable or marginalized populations,
including Indigenous peoples. Allocation of funding to LMIC by
international bodies should be targeted for building research
capacity and infrastructure and ensuring perennial development
and training of a research workforce. Funders should demand that
a portion of their awards be allocated to collaboration between
HIC and LMIC in the design and execution of studies. Appropriate
funding of researchers in LMIC and fostering real, transparent
research collaboration will decrease the power imbalance
and the dependence on HIC institutions, increase output and
representation of LMIC in data and result in substantial, inclusive
global dementia research.
Many countries do not prioritize dementia research at all,
and they should be encouraged and helped to change their
approach. As dementia is a global problem, research should be
global and include flows of funds and materials from higherto lower-resource settings. Incentives to undertake “cuttingedge”, innovative research should include government grants
and tax breaks. The use of research funds should be monitored
and a network of international and inter-agency collaboration
be created to reduce duplication of research and thereby reduce
waste. This does not refer to replication, which is usually necessary
to establish the validity of research findings and their applicability
to other settings.
Finally, funding should be equitably allocated to female researchers
in order to reduce the gender gap and counter the relatively fewer
grants and professorships awarded to female researchers.
2. Drivers of dementia research
9
2.4 Access to science, data and materials
Global dementia research could be improved by increasing access to scientific knowledge and by sharing protocols, procedures, data
and other research materials, including biological samples. Scientific sharing has many potential benefits.
Access to science
During the past decade, substantial efforts have been undertaken to make knowledge more accessible to the scientific
community, including researchers in LMIC. This is vital and must be sustained in order to make research publications widely
available, contribute to the democratization of science and overcome the financial barriers often faced by LMIC researchers and
institutions. Open access publishing has made research more accessible, although publication costs are often high. Publications
that can be accessed by paid subscription only are generally expensive and out of reach in low-resource settings. Global action is
necessary to address such inequity.
Data-sharing
Addressing challenges associated with dementia research requires collaborative efforts among stakeholders from all parts of the
world. Naturally, the ability to share data, or lack thereof, significantly impacts the progress in the dementia research field. With
recent scientific progress, substantial data is routinely collected in many research areas, including epidemiology, biomarker and
drug development and clinical trials.
Sharing of fully de-identified data on participants among research groups allows mega-data analyses and meta-analyses,
providing greater statistical power and answering many novel questions without collecting new data. Data-sharing thus
prevents unnecessary duplication of research and is essential for testing the reproducibility of findings. Sharing also encourages
better quality control, openness, greater scrutiny, research integrity and collaboration.
Data-sharing can be promoted and made possible through the creation or engagement with existing national dementia
registries, national and international databases of dementia research, an international drug development platform, an
international database of epidemiological data and a network of biobanks. This will require resources, infrastructure and policies
to promote safe, equitable and accessible sharing of high-quality data.
Internationally recognized policies should be developed for the quality, integrity, sharing, privacy and security of data. Potential
conflicts between open, accessible data and requirements for governance and ethical frameworks for the security and privacy
of research participants should be resolved. Robust policies on data privacy should be in place to sustain current and future data
acquisition and sharing. Regional work in this regard should be made global. Funding agencies should actively promote datasharing by providing incentives and making it mandatory, when possible, while acknowledging the intellectual and practical
work of the primary researchers and the importance of responsible, ethical use of data.
WHO has published policy and implementation guidance (5) on how to develop a data management and sharing plan for creating
digital datasets that are in line with WHO’s policy on the sharing and reuse of health-related data for research purposes, and
ensure an equitable, ethical, efficient and fair approach.
10
A blueprint for dementia research
2.4
Access to science, and materials continued
Sharing of materials, protocols and procedures
International regulations should be adapted or created to facilitate sharing of biological samples, imaging and other materials
among countries, while ensuring the safety, intellectual protection and privacy of people. Protocols for epidemiological studies
and trials, measures for assessment and outcomes of interventions, diagnostic criteria and guidelines for several topics (e.g.,
cognitive assessments, neuroimaging, fluid biomarkers and neuropathological assessments) must be developed and agreed by
consensus across experts from different parts of the world, input from people with lived experience, and shared with the research
community to support research capacity and standardisation of methods.
Pre-registration of research protocols with journals may reduce publication bias and ensure greater transparency and
reproducibility of findings. Sharing of protocols and procedures should respect local conditions, culture, language and legislative
requirements to ensure that research in dementia is consistent globally and adheres to the best international standards. For
example, countries and regions should develop, validate and adopt economically and culturally appropriate clinical assessment
instruments that are culturally and linguistically fair and readily accessible. This will require qualitative research to understand
local concepts of dementia-related variables and avoid de-facto translations of instruments developed in other contexts.
2.5 Capacity-building for research
Training programmes (e.g., fellowships, workshops, postgraduate
courses) to increase the capacity and capability of researchers
in all disciplines relevant to dementia research, particularly in
LMIC, would improve the quality of all dementia research. Gaps in
research (e.g., in understanding non-AD dementias in LMIC) should
be filled by training more personnel in the relevant disciplines or
establishing collaborations. National and international exchange
programmes, research-sharing platforms and collaborative
networks may be useful. The involvement of people with lived
experience organizations that support and represent them are
critical in such work.
to increase the possibility of collaborations. Likewise, engaging
with mental health researchers and workforce can help to build
capacity of researchers in understanding stigma and complex
interventions. A cross-disciplinary approach to research in which
basic scientists work with medical and allied health and related
disciplines will maximize the potential of dementia research.
As such requirements may be more challenging to meet in LMIC
than in HIC, funding should be provided to increase the research
workforce in regions. Enabling sustainable and fair collaboration
between HIC and LMIC institutions will also support capacity
building of researchers globally.
All researchers involved in dementia research, particularly those
who work directly with people with cognitive impairment, should
receive training in dementia and ageing and in identifying
early signs and symptoms of cognitive decline. Training could
be increased strategically in areas in which skills are lacking,
such as in basic science, epidemiology, cognitive assessment,
ethical research practice and dementia care. Non-dementia
researchers who work with older people with conditions such as
diabetes or heart disease could be trained in dementia research
The career paths of junior researchers should be considered.
Research careers are generally insecure, and the transitions from
doctorate to early career researcher and then to an established
researcher are challenging. Many promising junior researchers
that are unsupported and underfunded may seek alternative
careers, causing “brain drain” and a reduction in research capacity.
Better funding models and support systems are necessary to
address this problem internationally.
2. Drivers of dementia research
11
2.6 Technology
Technological advances present both opportunities and
challenges. Developments in areas such as computing and
wearable technologies, imaging hardware, intelligent design
and architecture, artificial intelligence and deep learning offer
opportunities to advance dementia research. For example,
wearable devices and smartphones, which are readily available
in both HIC and LMIC, can passively collect large amounts of
continuous real-time data that can be integrated and harmonized
by big data technology in a variety of sources and scales.
Global cooperation in the development and sharing of digital
biomarker technologies is essential. They include the technologies
used to acquire data (e.g., smart devices), store data (e.g., digital
infrastructures) and share data (e.g., robust ethical guidelines)
internationally. Another important application of technological
advances is for the development of tools and devices that support
activities of daily living and ensure security and safety of people
living with dementia. These must be developed taking into
account the specific needs of people living with dementia and
their potential cognitive impairments.
The “digital divide” both within and between HIC and LMIC must
be reduced. As technology is more likely to be used to collect data
in HIC, they disproportionately contribute to digital biobanks and
skew findings. Funding for research on digital biomarkers in LMIC
is imperative.
Researchers in HIC have taken advantage of big data technologies
and have developed data-driven approaches to dementia
prevention. They can process and manage such data quickly
and efficiently. Data-driven approaches like machine learning
algorithms and deep-learning frameworks are often not
available in LMIC because of their high cost. Access to digital
health tools and increased literacy in digital epidemiology in
digitally disadvantaged groups are therefore essential. Alternative
solutions should be found in regions where digital infrastructure
is not yet well established while an increase in investment into
digital infrastructure takes place.
Technology such as encryption and block chain can preserve
privacy. The development and application of machine learning
and artificial intelligence can enhance understanding of the
mechanisms, diagnosis and biomarkers of dementia. Digital
models may reduce animal experimentation and make
intervention trials more accessible. Technology can resolve
many issues of diversity and inequity in dementia research, but
only if a concerted effort is made to include all ethnic, regional
and socioeconomic groups.
2.7 Knowledge translation and exchange
To best help people living with dementia and their families and
carers, beneficial research findings must be applied as quickly
as possible in health practice and public health policy. There
are, however, considerable barriers (e.g., lack of awareness) to
translating even robust research. Moreover, implementation
can reveal unsuspected challenges; their resolution feeds into
knowledge creation, thereby providing bidirectional exchange
of information. Increasing the awareness, presence and standard
of implementation science is therefore critical to bringing the
benefits of research rapidly to the people who need it.
Building capacity and infrastructure for translating research
findings into practice for people living with dementia is necessary
12
A blueprint for dementia research
in public, research and private settings and in both HIC and LMIC.
Investment in capacity and infrastructure must come from all
these settings in direct international collaboration, including
sharing of resources and the benefits of implementation. This is
important for every country and region but particularly for LMIC
and subnational regions that may lack the necessary resources.
Dementia research is usually multidisciplinary, and the necessary
expertise in all areas may not be found in some settings.
International sharing of expertise can facilitate multi-component
research and collaboration. This will require formation of networks
to link diverse researchers and setting up databases and platforms
for sharing at local, national and international levels.
2.8 Regulatory environment
A strong, well-formulated and transparent regulatory
environment is a key driver of research and an important enabler
of collaborations and successful research implementation.
Complexity and lack of transparency in regulatory environments,
however, and divergent international norms and standards may
create barriers that will hinder the establishment of collaborations
and slow down the implementation of innovations. Creation of
ethically and morally sound guidelines that anticipate the evidence
and requirements necessary for regulatory review and policy
development would fast-track life-changing scientific advances.
Moreover, international harmonization of norms and standards
and international agreements can facilitate establishment of
worldwide collaborations, increase access to resources and avoid
future hurdles in regulatory and policy decisions.
2. Drivers of dementia research
13
© Worawee Meepian
3. Dementia epidemiology
and economics
3.1 Context
In 2019, an estimated 55.2 million people were living
with dementia (1). Dementia was the seventh leading
cause of death worldwide, accounting for 1.6 million
deaths in that year and contributed to 28.3 million
disability-adjusted life-years (8). Figures like these are
the basis for policy-making, allow resource planning
for the health and social care sector (both public and
private) and support the monitoring of secular trends
in dementia, identifying and understanding risk and
protective factors and research for new interventions.
Counting cases of dementia is complex, and estimates
of prevalence and incidence may depend on the study
design, sampling strategy, the age range included,
representation of minority groups, the quality of
population demographic data and the method used
for case ascertainment (9). Determining the number
of cases is further complicated by stigmatization of
dementia (10) and by changes in the diagnostic criteria
for dementia and its disease subtypes over time.
In the Global status report on the public health response
to dementia (1), it was estimated that the prevalence
of dementia in people aged ≥ 60 years ranged from
2.9% in the South-East Asia Region to 6.5% in the
European Region; other regional estimates ranged
from 3.1% to 5.7%. Fig. 4 shows the global dementia
prevalence, stratified by age group and sex. Women are
disproportionately affected by dementia, as reflected
by a greater prevalence among women than men in all
age groups, 60% more disability-adjusted life-years
due to dementia in women than in men and a higher
proportion of deaths from dementia among women (1).
Fig. 4. Global prevalence of dementia by sex and age group, 2019
40–59
0.2%
0.2%
0.2%
60–64
1.0%
1.1%
1.1%
65–69
1.9%
2.2%
2.1%
70–74
3.5%
4.3%
3.9%
75–79
80–84
85–89
21.9%
23.9%
18.4%
35.9%
39.0%
28.9%
Male
13.6%
15.0%
11.7%
90+
7.4%
8.2%
6.4%
Female
All
Source: Global status report on the public health response to dementia (1).
15
Current projections of the numbers of cases of
dementia are based on the assumption that agespecific prevalence rates are stable (11), consistent
with various estimates based on global data (12–14).
Evidence from HIC, however, suggests that dementia
incidence may be decreasing (15). This is not a global
phenomenon, and, in some countries, the incidence
appears to be increasing among more recent birth
cohorts (16). Globally, the number of people living with
dementia is likely to triple by the middle of the century
(13).
Various determinants of health influence the incidence
of neurological disorders, including dementia, during
the life course (17). For instance, the incidence of
dementia is affected by the prevalence of risk and
protective factors at population-level and the strength
of their association with dementia during the life course
as well as the timing of exposure to those factors.
Some risk factors are more prevalent than others and
account for more cases of dementia in LMIC than in
the rest of the world (18). While the risk and incidence of
dementia may ultimately decrease as concerted efforts
are made to address individual and population risk and
protective factors, persistent inequality may prevail,
with implications for the projected prevalence in those
populations (1). For more details on risk and protective
factors, see chapter 8.
The global societal cost of dementia can be calculated
from current prevalence rates. For instance, in 2019,
the annual global cost associated with dementia
was estimated to be US$ 1.3 trillion. On the basis of
population projections and corrections for inflation,
the cost is expected to reach US$ 2.8 trillion by 2030
(1). Approximately 20% of the cost of dementia is
attributable to direct medical costs, irrespective of
national income; however, the proportion of the costs
attributable to informal care in each country is much
higher in low-income countries (approximately 70%)
than in HIC (approximately 40%) (1). While the economic
benefits of preventing or slowing the progression
of dementia are obvious, methods to ensure cost–
effectiveness have been applied to dementia only
recently. The limited evidence suggests that
reducing exposure to risk factors (19), psychosocial
interventions (20) and medications (21) is cost-effective.
In addition, there is some evidence that psychosocial
interventions for carers are cost–effective (22, 23).
Developments in the field of dementia economics are
important in terms of planning health interventions and
care and resource development and for incentivizing
16
A blueprint for dementia research
Health and cost
estimate models
are only as accurate
as their input data
and are presently
seriously
limited.
governments, funders and service providers to invest
in effective approaches to reduce the risk of dementia
and for treatment and care for current and future
populations (20).
It should be noted that these estimates are only as
accurate as the data used in the models and are
seriously limited by the lack of data on prevalence,
disability, mortality and cost in certain parts of the
world. Improved datasets are necessary to increase the
accuracy and representativeness of the data.
3.2 Research gaps
Epidemiology
Lack of good-quality data
Many countries, both HIC and LMIC, do not have upto-date, high-quality, nationally representative data
on the prevalence or incidence of dementia derived
from epidemiological studies or administrative data
(24, 25). Data on young-onset dementia are very limited.
Insufficient diversity
Reliable data on differences in dementia rates among
people in, e.g., different ethnic and racial groups (9)
and in sexual minorities (26), are lacking, and the rates
in Indigenous peoples have rarely been measured (27).
Methodological issues
Many epidemiological studies are of poor quality,
with suboptimal implementation of multiphase
design (i.e., screening of all participants in the first
phase and diagnostic assessment of subsamples
in subsequent phases), small samples, suboptimal
recruitment of individuals with dementia, especially
those at moderate–severe stages, and/or lack of a
comprehensive diagnostic assessment for dementia.
Disease representation
Most of the available epidemiological studies do not
include data on biomarkers for subtyping dementia
and do not take into consideration that dementia is
often of mixed etiology.
Lack of standardization
Coding of dementia as the underlying cause of death
in registration of vital statistics is widely inconsistent
among countries and over time. Furthermore,
recording of dementia as a cause of death has
increased (28). These factors complicate estimation
of global mortality from dementia.
Economics
Lack of representative data
Few data are available from many parts of the world,
particularly LMIC. Even in countries with data, few
population-based cohort studies have been conducted
that represent diverse communities and include data
on resource use and costs. Consequently, most costing
studies have been based on clinical or convenience
samples and not on known populations. Many of the
studies that provide data were conducted only in a
limited geographical area where research capacity is
sufficient; however, the findings are often extrapolated
to whole countries and even regions.
Dependence on poor-quality prevalence data
The validity of global studies of the costs of dementia
relies directly on the quality of estimates of prevalence
and data on service contacts in each country. Variations
in the way in which dementia is diagnosed lead to highly
variable estimates of prevalence that affect estimates
of the cost of illness. Data on cost of illness are rarely
nationally representative and are particularly sparse in
LMIC (29).
Variation in the definition of informal care
Variation in the definition of informal care raises
several methodological challenges to estimating the
time spent caring, impacts on carers and how their
time is valued (30).
Lack of data on cost–effectiveness
While use of economic evaluation in dementia is
increasing, few studies of dementia risk reduction and
intervention have included cost–effectiveness in their
design (21, 31). Lack of such evidence is a considerable
barrier to wide-scale approaches to more effective
risk reduction and treatment. Cost–effectiveness
data are also necessary to incentivize investment in
effective interventions. Outcomes that matter to many
populations of interest are not well described, and this
is an important area of research.
3. Dementia epidemiology and economics
17
3.3 Strategic goals, actions and milestones
STRATEGIC GOAL 1
High-quality epidemiological data
Ensure availability of high-quality epidemiological data from widely representative geographical, ethnic
and socioeconomic groups with appropriate disaggregation by gender and sex, age, disease severity and
subtypes and relevant measures of inequity.
Actions:
Obtain high-quality, up-to-date, representative data.
Conduct epidemiological studies of dementia both in countries
with no data and in those for which data are outdated
or unrepresentative. Studies should be representative of
the populations in which they are conducted and should
ensure sufficient sampling and characterization of socially
marginalized groups, where applicable. Both cross-sectional
and longitudinal studies are necessary to obtain prevalence
and incidence data. Epidemiological studies should be repeated
and/or revised periodically to include changing trends in both
rates and risk factors.
Improve the quality of administrative data. Improve the
quality of data derived from administrative health systems
and the linkage between systems such as health and social
care data, for example by creating clearer guidelines for death
certification and unique patient identifiers and increasing
awareness of the mortality associated with dementia. New
methods could be used that do not rely on vital registration
data for calculating excess mortality (14).
Apply international standards. Follow international
benchmarks for methodological rigour in epidemiological
studies for dementia. The method and instruments used must
be adapted appropriately to the setting of the study, which
should include translation, cultural and contextual adaptation
and validation of instruments when necessary. WHO’s GATHER
guidelines (32) should be applied for accurate, transparent
reporting of health estimates.
Promote data-sharing. Promote the development and
coordination of sustainable international platforms for
sharing data, with appropriate standardization and privacy
(e.g., Alzheimer’s Disease Neuroimaging Initiative, the Global
Alzheimer’s Association Interactive Network, the Alzheimer’s
Disease Data Initiative, Dementias Platform UK and Dementias
Platform Australia).
Analyse risk and protective factors and burden of dementia.
Include analyses of associations with risk and protective
factors and their interactions throughout the life course in
all populations. Studies should accurately capture rates of
morbidity and mortality associated with dementia (33). Data
should be collected specifically in world regions for which there
are few data.
Milestone 1.1: By 2027, to have international
benchmarks for epidemiological studies and use of
open-access, inter-operable, international platforms
to archive and share epidemiological data from regions
around the world.
Include disease subtypes in epidemiology studies. Address
cognitive decline and dementia in all disease subtypes, and
include data on biomarkers when possible and if resources
permit.
Use other data sources. Use other sources of data to
complement epidemiological data in order to arrive at true
prevalence figures. These may include data on hospital
admissions for dementia, data from surveys in primary care
settings, records of prescription for anti-dementia medications
18
and data from surveys of long-term care facilities and aged
care services. Some such data may be obtained from national
administrative datasets collected routinely in many countries.
This can be considerably facilitated by establishment of
dementia registries (34).
A blueprint for dementia research
Milestone 1.2: By 2030, to have a comprehensive
dataset from high-quality epidemiological studies that
include geographical, ethnic and regional populations
for whom there are currently insufficient data to fill
major gaps in international data.
Milestone 1.3: By 2030, to have ensured that countries
have high-quality health administrative data to
monitor dementia and the quality of its assessment and
care.
STRATEGIC GOAL 2
Economic impact of dementia
Establish better understanding of the economic impact of dementia on society and generate robust
evidence on the cost–effectiveness of risk reduction, treatment and care.
Actions:
Build consensus on methods for measuring cost of illness. To
ensure meaningful synthesis of data globally, reach consensus
on the conduct of cost-of-illness studies in dementia, with a
focus on monetary valuation and definition of informal care.
Generate high-quality data on service contacts and costs.
Conduct research to understand and better estimate the cost
of dementia, including in regions and countries for which there
are no data.
Obtain evidence of cost–effectiveness. Promote research
to understand and identify WHO best buys1 for cost-effective
treatment, care and risk reduction. The research should account
for the fact that some investments take decades to yield
benefits but that they may have positive outcomes for healthy
ageing overall. The data should be relevant to all regions and
resource settings and different populations.
1
Include dementia as an outcome in other studies. Ensure that
studies on preventive interventions for other noncommunicable
diseases (NCDs) include dementia, or at least cognition as a
proxy, in modelling cost–effectiveness in view of the similarity
of the risk factors and comorbidity.
Milestone 2.1: By 2027, to have established a database
on burden of disease and cost estimates for dementia
from different geographical, ethnic and regional
groupings around the world.
Milestone 2.2: By 2030, to have generated robust
evidence on the cost–effectiveness of treatment and
care interventions and strategies to reduce the risk of
dementia to support establishment of public health
interventions throughout the life course.
Similar best buys have been developed for the prevention and control of noncommunicable diseases (NCDs). These WHO Best buys comprise a list of recommended and most
cost-effective interventions, including overarching/enabling policy actions. These include, for example, actions to reduce tobacco use and the harmful use of alcohol and the
promotion of healthy diet and physical activities.
3. Dementia epidemiology and economics
19
© janiecbros
4. Dementia disease
mechanisms and models
4.1 Context
Dementia consists of a group of symptoms (a
syndrome) associated with a variety of diseases
that share the development of progressive
neurodegeneration and cognitive decline (Table
2). The origins of and the mechanisms leading to
dementia are complex and multifactorial. During the
past three decades, major advances have been made
in understanding the pathophysiology of dementia,
and yet it remains poorly understood. Bridging this
knowledge gap will include identifying biomarkers for
timely diagnosis, accurate prognosis and monitoring
of progression. Dementia generally develops over
many years and is often diagnosed only when
significant neurodegeneration has already occurred.
Therefore, understanding of the different disease
mechanisms during the life course is crucial to identify
new therapeutic targets and develop treatments to
intervene earlier in the disease course.
A further complication is the frequent concomitant
occurrence of several diseases, particularly in older
adults, which makes it difficult to isolate the primary
causal factors. The overlap of some neuropathological
characteristics in different disease subtypes suggests
some common basis. For example, accumulation of
insoluble fibrillar forms of tau can be present in AD,
frontotemporal dementia and other tauopathies.
Recently, the importance of cerebrovascular
mechanisms has been recognized, some evidence
suggesting that vascular dysfunction may occur
early in the process of AD (35), although its role in
frontotemporal dementia and dementia with Lewy
bodies is less clear (36). While the overlap of conditions
in several subtypes may be seen as a complication
to understanding the underlying mechanisms, it
suggests that treatments targeted to those common
conditions could be beneficial in treating various
Table 1. The most common dementias and their distinguishing brain pathological features
Dementia
Approximate
proportion of all
dementias (%)
Alzheimer disease
60–80
Vascular dementia
13
Distinguishing brain pathological features*
Reference no.
Amyloid-β plaques and tau neurofibrillary tangles
37
Cerebrovascular pathology
38
α-Synuclein protein clusters
39
Dementia with
Lewy bodies
3.1–7.1
Frontotemporal
dementia
3.0
Frontal and temporal lobe atrophy, abnormal
tau, TDP-43, fused sarcoma protein
40
Dementia due to
Parkinson disease
3.6
α-Synuclein deposits
41
*Note that several features may be present, and different sources cite different single and multiple features.
21
diseases causing dementia, including rarer examples
such as Creutzfeldt-Jakob disease (36). It might also
indicate that a combination of therapies is required
according to the molecular signatures of the diseases
of each person with dementia.
Most research to date has addressed the most
common disease subtype causing dementia, AD, in
which causative autosomal dominant gene mutations
are found in three genes in some extremely rare
cases of familial early-onset disease (42). For the
more prevalent clinically diagnosed late-onset AD
(which is likely to include various other age-related
conditions), in addition to the apolipoprotein E ε4
allele, more than 70 genetic loci have been identified
that increase risk (43, 44). In order to use the results
of these genetic studies to identify viable targets,
the mode of action of genetic risk factors must
be understood, with identification of their protein
products and/or how they affect molecular processes
relevant to the disease. Research on the pathological
mechanisms leading to AD has mainly addressed its
hallmarks: accumulation of amyloid beta plaques and
neurofibrillary tangles in the brain. Population-based
neuropathological studies have shown that most older
people have these changes in their brains irrespective
of whether they express dementia clinically. The
amyloid cascade hypothesis has dominated the
research field (45), and strategies to reduce amyloid and
tau have been tested in many clinical trials. Because of
the continued failure of trials of strategies targeting
amyloid plaques, however, the amyloid hypothesis
Research on
the pathological
mechanisms of AD
mainly addressed its
hallmarks:
amyloid plaques
and neurofibrillary
tangles.
22
A blueprint for dementia research
has recently come under increased scrutiny. Although
the role of amyloid-β accumulation and tau tangles
is supported by substantial evidence, it has become
apparent that a more holistic approach is required
to understand the molecular underpinnings of AD
etiology.
Alternative and/or additional pathways leading
to disease have been studied, including
neuroinflammation, excitotoxicity, oxidative stress,
mitochondrial dysfunction, lysosome degradation,
immunity, ubiquitination, cholesterol transport,
glial activation and neurotrophic factors (44, 46). The
contribution of each of these mechanisms and
the interactions among disease-related pathways
and amyloid or tau are still poorly understood.
Furthermore, increasingly, a comprehensive view is
being taken to understand the roles of factors such
as sleep disruption, the microbiome and infection
(e.g., virus, bacteria, prion) in the development and
progression of AD (46). As ageing is a common risk
factor for dementia and other chronic diseases, it is
important to understand ageing and the mechanisms
by which it promotes disease. This complex set of
factors that affect diseases and cause dementia also
make it difficult to develop ecologically valid animal
models of the various subtypes of dementia, including
AD (47). Furthermore, the findings from animal models
and ex-vivo models e.g., stem cells, tissues as well as
biofluid analysis must be validated, as these reflect
only some aspects of this complex disorder.
Understanding the molecular mechanisms of diseases
other than AD that cause dementia and the interplay
among different conditions is also important. The
term “vascular cognitive impairment and dementia”
is used to describe vascular dementia and predementia cognitive impairment that is attributed to
cerebrovascular pathology (38). Vascular dementia
is the second most common type of dementia.
Dementia with Lewy bodies is another common form,
associated with accumulation of Lewy bodies (39).
Likewise, Lewy bodies also occur in Parkinson disease,
in which there is a strong likelihood of dementia over
time. Frontotemporal dementia is a heterogeneous
disorder with diverse clinical symptoms, underlying
conditions and genetic architecture. It is rare and
is often expressed as early-onset dementia (48). The
pathological mechanisms of less common dementias,
such as those caused by Huntington disease,
corticobasal degeneration, progressive supranuclear
palsy and prion diseases, are also being investigated,
including their possible overlaps with each other
and with more common diseases causing dementia
(49). Finally, sex is a source of disease variation in
AD (50), dementia due to Parkinson disease (51) and
frontotemporal dementia (52).
Altogether, it is paramount to improve our knowledge
of the underpinnings of the diseases causing
dementia. More studies on the mechanisms underlying
these diseases will not only improve understanding
about the origins of these neurological disorders but
also form the basis for development of diagnostics
and therapeutic strategies.
4.2 Research gaps
Pathological mechanisms
Complete understanding of protein-associated
pathological mechanisms
While robust evidence has confirmed the association
of amyloid-β and tau with AD, their role in disease
development and progression and their association
in the complex environment of the brain is not
completely understood. The degree to which Lewy
bodies themselves cause dementia is also unclear, as
they frequently occur in AD-type conditions.
Other pathways
The role of other pathogenic pathways, such as
neuroinflammation, oxidative stress and other
downstream effects, and their consequences
and representation in disease models is not fully
understood and should be further explored, including
their potential role as targets for therapeutics (see
chapter 6).
Pathophysiology of AD
While considerable research has been conducted on
the amyloid cascade hypothesis in AD, its integration
with genetic and environmental risk factors and other
diseases during the life course requires more complex
models of pathogenicity which are presently lacking.
Pathophysiology of diseases other than AD
Little research is conducted on the pathological
mechanisms of non-AD dementias, such as dementia
with Lewy bodies and frontotemporal dementia, which
are poorly understood.
Molecular contribution of risk factors
Although several comorbid conditions and health
determinants have been identified as risk factors for
dementia (e.g., cardiovascular disease and obesity),
further research is required on the molecular relations
among these diseases and their impact on dementia
development.
Contribution of vascular aspects
There is currently an incomplete understanding of
vascular contributions to dementia and a need to
translate findings into the development of effective
interventions that are accessible globally.
Biological causes of behaviours and
psychological symptoms associated with
dementia
Little is known about the biological mechanisms
underlying behaviours and psychological symptoms
associated with dementia.
Contribution of several conditions
Several pathological elements can coexist in the same
individual (e.g., amyloid-β, tau, α-synuclein, TDP-43),
but there is limited understanding of how and whether
they interact.
Deeply phenotyped cohorts
Inadequate information is available on extensively
phenotyped cohorts for studying disease mechanisms
in humans. Many of the studies were performed
by private entities, and, with very few exceptions,
the data are not freely available to the scientific
community.
Geriatrics and the contribution of biological
ageing
Ageing is the major risk factor for dementia; however,
its biological role in disease development is poorly
understood. There is a lack of collaboration between
geriatricians and other disciplines (e.g., neuroscience
and neurology) (53, 54).
4. Dementia disease mechanisms and models
23
Lack of genetic and ethnic diversity
Genetic research has been conducted mainly in HIC
and populations of European origin. Studies of diverse
populations, particularly life course cohorts, would
provide new insights into the origins of diseases
causing dementia and the role of genetics in dementia
development.
Sex differences
Men and women appear to differ in biomarker patterns
and clinically in different forms of dementia. The
contribution of the genetic, hormonal and societal
roles of sex and gender as risk factors for dementia is
not well understood and could provide new insights
into the mechanisms of the diseases.
24
A blueprint for dementia research
Resilience and compensation mechanisms
The underlying mechanisms of reserve, resilience
and compensation (e.g., education, physical exercise)
are often not included in investigations of disease
mechanisms.
Disease models
Limited experimental models are currently available, and
they do not reflect the complexity of neurodegeneration
observed in the human brain and body. Models of a
single aspect of a disease are usually not ecologically
valid. Moreover, animal models have been designed
primarily for AD, and there are few models of other
dementias or mixed dementia conditions.
4.3 Strategic goals, actions and milestones
STRATEGIC GOAL 3
Understanding underlying diseases
Increase understanding of the origins and mechanisms of the diseases that cause dementia through a
life course approach.
Actions:
Mechanisms of monogenic diseases causing dementia.
Conduct more research on the disease mechanisms that are the
basis of neurodegeneration and symptoms, and that are caused
by single-gene mutations (e.g., autosomal dominant AD, some
frontotemporal dementias, Huntington disease).
Complex multifactorial mechanisms in dementia. Investigate
the contributions of multiple pathogenic pathways to dementia
(e.g., protein aggregation and toxicity, neuroinflammation,
excitotoxicity, oxidative stress, mitochondrial dysfunction,
lysosome degradation, immunity, ubiquitination, cholesterol
transport, glial activation and neurotrophic factors) considering
ageing, environmental and lifestyle risk factors and genetic
background. Longitudinal studies with deep characterization
of participants by, e.g., imaging, biomarker profiling and omics
technologies (e.g., genomics, transcriptomics, proteomics and
metabolomics) are essential.
Biological causes of behaviours and psychological symptoms
associated with dementia. The biological causes of behaviours
and psychological symptoms associated with dementia should
be investigated as background for the design of therapeutic
interventions to be incorporated into care models (see chapter 7).
Molecular impact of risk factors. Promote both preclinical and
clinical research to understand the molecular influence of risk
factors such as comorbid conditions and health determinants on
the development of dementia.
Sex differences. Study the role of biological sex differences in
the diseases that cause dementia, biological ageing and risk
and protective factors throughout the life course.
Molecular profiles in the brain: Map the molecular profiles of
different brain cell populations (e.g., neurons, glia) for spatial
and chronological characterization of vulnerable brain cell
systems affected in dementia.
Technological innovations. Use recent technological innovations
in omics technologies, neuroimaging, computational science and
artificial intelligence to better understand the mechanisms of
dementia, and develop new technologies in partnerships with
academia, government and private enterprises.
Research collaborations and partnerships. Provide funding
and support for collaborative interdisciplinary research in
fundamental neuroscience through to clinical studies to
address the complexity of these disorders. Partnerships among
researchers, clinicians, consumer bodies, government and
private industry should be facilitated.
Brain banks. Create a global coalition of brain banks to
facilitate research into the pathology of diseases causing
dementia across several countries and ethnic and racial groups
and promote equitable access to such resources around the
world. Currently, brain bank consortia tend to be national
or regional (e.g., BrainNet Europe, US National Institutes of
Health NeuroBiobank). Funding should be provided for the
establishment of brain banks in LMIC.
Longitudinal studies. Bring together existing international
cohorts and establish new cohorts with innovative approaches
and appropriate inclusion of under-represented communities.
Birth cohorts and multigenerational cohorts are necessary to
understand the developmental aspects of diseases causing
dementia and potentially different risk profiles according to
generation. Deep phenotyping of cohorts should be conducted
with the currently available technologies, with exploration of
sex and gender differences. Global collaboration, open access,
sharing of data and pooling of resources are essential, including
data from industry-sponsored trials, which are currently not
readily accessible.
Milestone 3.1: By 2027, to have developed an
international collaborative network for sharing basic
scientific data and techniques, technical innovations
and materials that includes both HIC and LMIC,
academia, government and industry.
Milestone 3.2: By 2027, to have established new life
course cohorts to investigate the development and
progression of various diseases causing dementia.
Milestone 3.3: By 2030, to increase understanding of
the cellular and molecular mechanisms (e.g., protein
aggregation, inflammation, lysosomal dysfunction,
oxidative stress) of the different diseases causing
dementia and the relevance of determinants and
pathways throughout the life course.
4. Dementia disease mechanisms and models
25
STRATEGIC GOAL 4
Models of diseases
Develop models of the diseases that cause dementia that reflect their complex mechanisms and
downstream molecular events.
Actions:
Behavioural models. Develop new, standardized, highthroughput, unbiased behavioural platforms.
Better ex-vivo and computational models. Develop novel,
diverse, ecologically valid experimental models of diseases
that cause dementia to better understand the mechanisms of
neurodegeneration. The models could include stem-cell-based,
3D bioprinting, cerebral organoids and computational models.
26
A blueprint for dementia research
Animal models. Develop animal models that reflect the
complexity of dementia and represent the many molecular
events in disease development, including biological ageing,
protein aggregation and interaction, inflammation, lysosomal
dysfunction and oxidative stress.
Milestone 4.1: By 2030, to have improved ex-vivo
and animal models that represent molecular disease
characteristics and phenotypes, and are ecologically
valid for dementia in humans and underlying diseases.
© FatCamera
5. Diagnosis of dementia
5.1 Context
Timely, accurate diagnosis of dementia potentially
allows early intervention, action on modifiable risk
factors, better management of symptoms, support for
people living with dementia and their carer and families,
planning for the future, maintenance of independence
and postponement of institutionalization (55, 56). From
the perspective of research, it is also important
for recruitment and stratification of clinical trial
participants and accurate assessment of the
effectiveness of new therapeutic interventions. The
global action plan on the public health response to
dementia 2017–2025 (4) includes the target of 50%
of countries reporting that at least 50% of cases of
dementia are diagnosed. Most countries, however,
have not reached this target (1, 57); the global rate of
undiagnosed dementia is up to 75% and may be as
high as 90% in some LMIC (39).
The average time from onset of symptoms to clinical
diagnosis is unduly long, at almost 3 years for lateonset dementia and 4.4 years for early-onset dementia
(58). The global COVID-19 pandemic has further delayed
access to diagnostic assessment, and the full impact
is yet to be determined (39). Accurate diagnosis of
dementia and the disease subtype requires a trained
workforce and dementia-specific clinical guidelines,
equipment, standards and protocols; however, fewer
than two thirds of the countries included in WHO’s
Global Dementia Observatory reported having such
guidelines and standards (1). Misdiagnosis of the
disease subtype is common; it is estimated to be
about 30% when confirmed post mortem, and 25%
of AD diagnoses must be adjusted after an amyloid
PET scan (39).
Although timely and accurate diagnosis of dementia is
extremely important, there is an increasing emphasis
on recognising neurocognitive disorders at the
prodromal stage of dementia including mild cognitive
impairment (MCI) and even subjective cognitive
decline (SCD) when no cognitive impairment is
objectively documented (59, 60). While the identification
of people at increased risk of developing dementia
28
raises the possibility of implementing strategies to
slow progression and delay the onset of dementia,
the sensitivity and specificity of diagnosis during
prodromal stages remain poor. Accurate identification
of individuals at these stages is increasingly based
on evolving biomarker science, which so far has been
used mainly to identify clinically applicable biomarkers
for AD and not for other disease subtypes. Biomarkers
are commonly investigated in cerebrospinal fluid
and blood, and the investigations usually consist
of the identification and quantification of abnormal
amounts of proteins (tau and amyloid) and markers
of neurodegeneration and neuroinflammation (61,
62). Likewise, genetic biomarkers for both early- and
late-onset dementia could improve diagnosis and
prognostication, including identifying individuals at
risk of progression from mild cognitive impairment
to dementia (63). Given the limited evidence on many
biomarkers and their availability only in some highresource settings, their clinical application at the
prodromal stage or even at dementia stages should
be further developed and validated.
Diagnosing dementia is extremely complex. Several
approaches, including the emerging biomarkers,
are being used, although much remains to be done.
A standardized neuropsychological assessment is
valuable for the diagnosis of mild cognitive impairment
and the early stages of dementia and may include
subtyping, assessment of progression and planning of
treatment and care. Several attempts have been made
to harmonize assessments so that the same tests and
normative data are used (64–67). Structural imaging,
including computed tomography (CT) and magnetic
resonance imaging (MRI), is an important component
of initial evaluations of early dementia. Significant
advances have also been made in functional imaging
with positron emission tomography (PET) (39),
including the finding of new amyloid and tau ligands,
and other tools, such as dopamine transporter imaging
and cholinergic PET for identification of underlying
diseases such as Parkinson disease and dementia with
Lewy bodies (41, 61, 68–70). There is growing interest in
identifying behavioural phenotypes of dementia with
ubiquitous, accessible technology (e.g., smart phones,
rings) to derive continuous personal data for early
diagnosis and subtyping (71, 72).
In view of its complexity, diagnosing dementia requires
an integrated, multifactorial approach in which clinical
examination is combined with neuropsychological,
imaging, fluid biomarker and genetic data sources. By
studying the time course of disease and monitoring
how different indicators of disease change over
time, diagnostic tools could be developed to
better understand disease stages, identify tailored
interventions and provide more accurate prognoses.
Barriers in health systems, such as lack of services
and a trained workforce, also affect access to and the
quality and sustainability of timely, accurate diagnosis.
These barriers are further discussed in chapter 7.
5.2 Research gaps
Cross-cutting gaps
High-quality data
There is a lack of high-quality data on time of diagnosis,
accuracy, subtyping and optimal diagnostic tools used
in primary care settings.
Standardization of assessments
Assessments for dementia in primary care are not
always optimal for the resource setting, are not
standardized or do not account for the diverse
socioeconomic and cultural backgrounds and
literacy of the population. The potential trade-off
between adaptation and standardization requires
a sophisticated, coordinated approach in order to
achieve both.
Neuroimaging
Structural imaging implementation in clinical
practice
Structural imaging (CT and MRI) is still used clinically
to rule out associated conditions rather than to rule
in dementia and its disease subtypes. Most major
advances in MRI technology have not been used in
clinical practice, and new and emerging MRI techniques
such as diffusion, perfusion and functional imaging
should be further explored for clinical application. MRI
Diagnosing dementia
requires combining
clinical examination
with neuropsychology,
imaging, fluid
biomarkers and
genetic
information.
has not been used for prognosis or in clinical trials on
various disease subtypes. Few efforts are under way
to develop portable, low-field MRI scans to increase
access (73).
PET imaging techniques
Molecular PET imaging developed for AD and dopamine
transporter imaging are useful for diagnosing dementia
with Lewy bodies and dementia due to Parkinson
disease, but its use for other disease subtypes and
other factors such as neuroinflammation and synaptic
integrity should be explored. Insufficient evidence is
available on suitable markers and PET radioligands for
measuring aspects such as neuroinflammation.
Machine learning in imaging
Reporting of neuroimaging requires experts who
evaluate a limited range of the information available
from the scans. The use of machine learning and other
artificial intelligence techniques is not widespread,
and there are few tools that do not require a highly
trained workforce.
New techniques
Newer imaging techniques, such as magnetic
particle imaging, and novel tracers (e.g., based on
nanoparticles) are still being developed for clinical
application.
Fluid biomarkers
Cerebrospinal fluid biomarkers
Although significant advances have been made in the
development of cerebrospinal fluid biomarkers for AD
(Aβ42/Aβ40, pTau, tTau) and neurodegeneration (NfL),
5. Diagnosis of dementia
29
little is known about biomarkers for dementia with
Lewy bodies, neurogenerative diseases associated
with TAR DNA-binding protein-43 (TDP-43),
vascular dementia and others or about markers for
neuroinflammation, synaptic loss and other processes.
Blood biomarkers
The validity and reliability of biomarkers in blood
plasma (e.g., pTau isoforms, Aβ42/Aβ40, NfL, GFAP)
and in cerebrospinal fluid is not yet fully established.
The assays used are not standardized, which would
minimize inter-laboratory variation and ensure
clinical robustness. Little is known about longitudinal
changes in these biomarkers and how they are related
to disease progression, as well as changes in PET,
atrophy and cognition. International consensus should
be reached on the methods and reference ranges
applicable to diverse populations.
Other fluids
The use of other types of fluids (e.g., nasal swabs) is still
not backed by evidence and requires methodological
and clinical validation to determine what they might
offer over and above cerebrospinal fluid and blood.
New biomarkers
Longitudinal analysis of cohorts is not common;
however, this could facilitate the identification of
biomarkers for the different diseases that can cause
dementia, even in the prodromal stages. Omics
technologies could be used to identify other proteins,
lipids or RNA as potential biomarkers.
Genetic biomarkers
Diversity
Little research has been undertaken on diverse
populations, especially in LMIC.
Non-AD genetics
Diseases other than AD are under-researched,
particularly with transcriptomics and epigenomics,
and the specificity of genetic biomarkers for different
types of diseases causing dementia is unclear.
30
A blueprint for dementia research
Genetic variation
How variations in genetics and mutations lead to
disease is insufficiently explored in research.
Sex differences
Genetic risks according to sex have been so far
inadequately studied.
Ethics
The ethical implications and psychological impact
of disclosure of genetic risk profiles are not well
understood. This is an important consideration for
genetic tests that are available to the general public.
Neuropsychological assessment
Complexity of assessment
Current tools require trained personnel
(neuropsychologists), are time-intensive, are not
adapted to different cultures and languages and lack
appropriate normative data.
Prediction of dementia
Little is known about the role of subjective cognitive
complaints or concerns in the prediction of future
dementia or of the factors involved in the progression
from subjective cognitive decline to mild cognitive
impairment to dementia.
Technology
Current technologies such as for remote assessment
and computerized testing have not been adequately
validated against traditional methods and are not
always accessible in low-resource settings, even after
validation.
Sex differences
Differences by sex in neuropsychological assessments
are not well understood or used to optimize diagnosis.
5.3 Strategic goals, actions and milestones
STRATEGIC GOAL 5
Development of biomarkers
Develop highly sensitive, specific diagnostic biomarkers for dementia that are cost–effective and can
distinguish the underlying diseases that cause dementia.
Actions:
WHO target product profile (TPP) or preferred product
characteristics (PPC). Develop a TPP or PPC to provide guidance
to funders, researchers, product developers and regulatory
agencies in the development of diagnostic tools by accounting
for access, equity and affordability at all stages of innovation.
Imaging biomarkers. Further validate and standardize
imaging biomarkers for diagnosis and monitoring of disease
progression. Promote research into new imaging biomarkers,
taking into account the molecular mechanisms of the different
diseases causing dementia. Ensure that throughout the
development process, safety, accessibility, and affordability are
considered as well as their implementation in different resource
settings.
Blood biomarkers. Promote research on the correlation
between blood biomarkers, disease progression and other
biomarkers (e.g., imaging). Studies should also be conducted
to assess the best combinations of clinically relevant blood
biomarkers that yield the greatest benefit for diagnosis,
prognosis, treatment and care. The studies must ensure
appropriate representation of different populations and account
for intra-day, between-day, biological variations, and disease
subtypes. Studies of blood biomarkers should also address the
use of different protein isoforms and conformations as potential
biomarkers of diseases and their correlation with basic primary
care assessments, clinical presentation and disease progression.
Genetic biomarkers. Support large-scale studies to identify
genetic biomarkers of the different disease subtypes, with
appropriate representation of populations for whom data are
currently lacking. The studies should include correlation with
other clinical assessments and biomarkers, and the methods
should account for sex differences.
Digital biomarkers. Increase research on digital biomarkers
of early dementia phenotypes, potentially with novel artificial
intelligence strategies (e.g., machine and deep learning) and
wearables, smart devices, cognitive measures and non-digital
biomarkers (74, 75). New digital solutions should not create
barriers for implementation and use in clinical practice in
different regions.
Scalability and diversity. Conduct studies to determine the
feasibility of scaling up work on fluid, blood and genetic
biomarkers for clinical use and trials, and design strategies to
ensure inclusion of diverse populations, LMIC and populations
of low socio-economic status in such studies.
Precision medicine approach to biomarkers. In view of interindividual variation, all biomarkers used for diagnosis should
be studied using a precision medicine approach to facilitate
identification of disease subgroups for tailored treatment, as is
currently done for certain types of cancer such as breast cancer.
New technologies. Develop new platforms, scanners, assays
and other techniques to find new, more accessible diagnostic
tools.
Milestone 5.1: By 2027, to have developed an affordable
test for diagnosis of AD that is acceptable worldwide.
Milestone 5.2: By 2030, to have developed affordable
tests for diagnosis of non-AD dementias such as
dementia with Lewy bodies, frontotemporal dementia
and neurogenerative diseases associated with TDP-43.
5. Diagnosis of dementia
31
STRATEGIC GOAL 6
Development of clinical assessments of cognition and function
Develop or improve clinical assessments of cognition and function that are applicable to diverse settings
and cover the entire disease spectrum.
Actions:
Development and validation of tools. For LMIC and diverse
populations, validate evidence-based, culturally appropriate
instruments for cognitive and functional assessments that can
be used in primary care and provide appropriate normative
data while prioritizing non-proprietary diagnostic tools to
improve access. Develop screening tools that are sensitive
and discriminatory in the prodromal or early phases for use in
primary care of older populations and people presenting with
cognitive decline.
Novel technologies. Promote research into novel technologies
to improve clinical assessment and monitoring of disease
progression, including cognition, function and behaviour, and
integrate the results with data from wearables, smart devices,
cognitive measures and biomarkers. Promote the development
of artificial intelligence and data science technology that is
culturally fair and adaptable to local conditions.
Remote assessments. Support research to validate remote
dementia assessments (e.g., telemedicine via computers and
smart devices) that are easy to access and adaptable to various
resource and cultural contexts.
Global consortium. Establish a global research consortium for
clinical assessment of cognition and function with equitable
regional representation to evaluate and monitor emerging
evidence, and curate resources for sharing knowledge.
Milestone 6.1: By 2027, to have developed and
incorporated into existing digital platforms curated
clinical assessment tools for dementia diagnosis that
are open access, used in primary care, culturally fair and
readily adaptable to different contexts.
STRATEGIC GOAL 7
Diagnosis during prodromal stages
Improve understanding and diagnosis of prodromal stages of diseases causing dementia and of the
clinical, legislative and economic implications of such diagnosis.
Actions:
Implications of diagnosis during prodromal stages.
Conduct rigorous research to establish the possible benefits
and potential harms, including costs and the social, legal
and insurance implications, of diagnosing diseases causing
dementia in their prodromal stages.
Markers during prodromal stages. Identify readily accessible,
scalable markers to anticipate progression (or not) to dementia.
Long-term cohort studies may be necessary to establish such
markers.
32
A blueprint for dementia research
Diversity. Account for the socioeconomic, ethnic, and sex/
gender diversity of populations when investigating different
disease pathways and consider how these affect the accuracy of
diagnosis during the prodromal stages of dementia.
Milestone 7.1: By 2030, to have developed diagnostic
benchmarks for diseases causing dementia at the
prodromal stages (such as mild cognitive decline
and subjective cognitive decline) that are applicable
in diverse settings and are identified by accessible
markers.
© gorodenkoff
6. Drug development
and clinical trials for
dementia
6.1 Context
As mentioned in section 2.3, the cost of bringing a
new drug to market approval is prohibitively high,
and, although many large pharmaceutical companies
have halted their efforts around dementia, interest in
the field is being renewed by collaborations among
industry, academia and governments. Examples are the
Alzheimer’s Prevention Initiative, the United Kingdom
Dementia Consortium, the Accelerating Medicines
Partnership – Alzheimer’s Disease, the European
Union Joint Programme – Neurodegenerative Disease
Research and the Davos Alzheimer’s Collaborative. In
a recent review (77), 143 agents were identified in 172
clinical trials on AD listed in the www.clinicaltrials.gov
database, of which 83.2% were putatively diseasemodifying drugs, 9.8% cognitive enhancers and
6.9% for treatment of neuropsychiatric symptoms.
Of the different drugs, 31 were in phase-III, 84 in
phase-II and 30 in phase-I trials. Of the drugs under
34
investigation, 37% were repurposed. Drug repositioning
and repurposing has been recognised as a valuable
alternative route for effective treatments. A Delphi
consensus in 2018–2019 identified several candidates
for repurposing (78) and described potential use of
transcriptional signatures from cells in various diseases
to identify candidate drugs.
Drug development for vascular cognitive impairment
and dementia has been limited to treatment or
prevention of small- and large-vessel disease or
post-stroke interventions and some symptomatic
treatment of cognitive impairment (79). Some studies
have approached the prevention of dementia by
preventing strokes on the basis of the shared risk
factors for vascular cognitive impairment, dementia
and stroke (80). Fewer drugs have been developed for
other diseases that cause dementia. For example,
in 2019, www.clinicaltrials.gov listed eight agents in
clinical trials for dementia with Lewy bodies, which
included some disease-modifying drugs (81). Several
disease-modifying drugs for frontotemporal dementia
are now in phase-II trials (82), but results will only be
available in several years.
The approaches to treatment development have
thus far largely focused on single molecules or other
treatments with a specific disease focus, such as
immunotherapy for specific disorders or targeting
specific enzymatic pathways. However, different
underlying diseases often contribute to dementia
development, progression and disease phenotypes.
Even when one, such as AD, is the cause, many
pathways are involved. It might therefore be necessary
to intervene at several pathways or several points on
the same pathway to achieve clinically meaningful
benefits (83). Consideration should therefore be given
to developing combination treatments delivered
simultaneously or sequentially.
© serts
There are few effective drug treatments for dementia.
Only four drugs are currently available internationally
for AD (1): three acetylcholinesterase inhibitors and one
N-methyl-D-aspartate receptor antagonist, and all are
symptomatic treatments, with no disease-modifying
properties. Since 2002, when memantine was approved
for moderate-to-severe AD, no new drug has been
approved. The only exception is the accelerated
approval of a monoclonal antibody against amyloid β –
aducanumab – by the US Food and Drug Administration
in 2021 on the basis that it removes amyloid from
the brains of people with AD and may have cognitive
benefits. The approval is controversial for several
reasons, not the least because cognitive benefits
have not been conclusively established, adverse
effects are significant, and there is no strong evidence
in this specific case that the removal of amyloid is
associated with clinical benefits (76). Drugs for treating
the neuropsychiatric symptoms of dementia, which
are often difficult to manage, also remain inadequate.
More attention should also be paid to the precision
medicine approach, whereby a treatment is tailored
to a patient’s specific condition. Much of the delay
in this field is due to pooling patients with different
conditions and testing the same drug in all of them
(e.g., amyloid-negative individuals in amyloid-lowering
trials). Addressing this requires the use of diseasespecific biomarkers and their development for other
dementia-related conditions is essential.
New therapies are necessary to improve the lives of
people with dementia and their carers. An appropriate,
better coordinated regulatory environment must
provide transparent guidance to developers,
streamline regulation and identify clear requirements
for the approval and release of drugs. The return on
investment and cost–effectiveness of therapies must
also be investigated, as discussed in chapter 3.
6.2 Research gaps
Multiple underlying diseases
Dementia is associated not with one but with
many diseases that may have different causes and
potentially an additive effect. Better understanding
these associations is essential to develop effective
therapies, perhaps with several targets.
The drug development pipeline for AD does not
reflect its complex, diverse mechanisms
While major advances have been made around AD, major
gaps remain in understanding the pathophysiological
process and the relation between pathology and
clinical presentation. Although non-amyloid pathways
in AD, including tauopathy, neuroinflammation,
oxidative stress and synaptic loss, are also being
addressed with diverse strategies, the interaction
of these pathways and how different treatment
strategies should be combined for synergistic effects
are not well understood. Better understanding of the
mechanisms, including the underlying causes of the
diseases, and the biological causes of behaviours and
psychological symptoms associated with dementia
is required to identify targets and ensure effective
treatments (see chapter 4).
interventions should be made as early as possible,
when and how to introduce interventions and whether
they differ according to the underlying disease, the
presence of comorbid conditions, genetic background
and sex remain to be understood.
Suboptimal clinical trial design
Due to the slow evolution and progression of dementia
symptoms, clinical trials for assessing the prevention
(see chapter 8), treatment or cure of dementia are
natually long. This makes clinical trials very expensive
and prone to high rates of attrition. More adaptive
clinical trials should be conducted, and clinical trial
networks should be established to make trials more
feasible, equitable and inclusive. This will require
engagement of research beneficiaries and the general
public.
Underrepresentation in clinical trials
Research on drug development and clinical trials
lack population and geographical diversity (84).
Even in HIC, socially marginalized populations are
usually under-represented. The pharmacokinetics
and pharmacodynamics of drugs in many populations
are therefore not well studied, resulting in inequity.
Despite being at greater risk of developing dementia,
women are under-represented in clinical trials for
AD (85).
Insufficient collaboration
Drug development is an intensely collaborative
exercise. It requires partnerships among scientists,
pharmaceutical companies, clinical trialists, health
specialists and service providers. Collaborative
networks should include academia, industry and
government, and trials should be truly international.
Such collaboration and networks are only just starting
to be established.
Involvement of people with lived experience
The research beneficiaries, i.e., the people living with
or at risk of cognitive disorders and their carers, must
be central to any study and be involved in all stages.
Consumer involvement is not the norm in many
jurisdictions.
Timing of interventions
The diseases that cause dementia often occur many
years before the onset of any clinical symptoms and
the timing of an intervention is likely to be crucial in
determining its success. Although many agree that
6. Drug development and clinical trials for dementia
35
6.3 Strategic goals, actions and milestones
STRATEGIC GOAL 8
Development of novel therapies
Develop novel molecules, repurpose drugs currently in use or newly developed and investigate nextgeneration biotherapeutics for effective treatment of dementia.
Actions:
Multiple targets. Promote research to investigate both
amyloid and non-amyloid targets and the biological causes
of behaviours and psychological symptoms associated with
dementia, and consider diverse populations, different sexes,
different genetic backgrounds and comorbid conditions.
Investment in non-AD therapeutics. Increase investment in
the development of treatments for diseases causing dementia
other than AD, including Lewy body disease and frontotemporal
dementia.
Novel approaches. Develop next-generation therapeutics
that target the cell, gene or nucleotide and treatments that
target brain networks for resilience, maintenance and repair for
dementia in general as well as specific pathological processes.
Other novel approaches such as antimicrobial treatments, the
gut–brain axis (including nutritional interventions), stem cell
therapy, brain stimulation and parabiosis should be further
investigated.
Combination therapy. Increase research on combination
therapies for dementia that target the many pathways
involved.
Complex disease mechanisms. Include consideration of the
complex mechanisms of diseases underlying dementia in the
design of therapeutics and the results of the actions proposed
in chapter 4. This is also applicable to the four actions above.
Cognition as an outcome. Include cognition as a secondary
outcome of trials for treatments of NCDs (e.g., diabetes,
mellitus, hypertension, coronary artery disease, stroke) to
explore the potential role of these treatments in cognitive
disorders and to identify new drugs and drugs that could be
repurposed for the treatment of dementia.
Precision medicine. Apply the principles of precision medicine
in dementia research to verify both the efficacy of a treatment
and the reliability of specific biomarkers.
36
A blueprint for dementia research
Access, safety and capacity. At all stages of treatment
development, integrate consideration of access, equity,
affordability and health system capacity to provide the
treatment.
Collaboration. Strengthen local and national networks that
link researchers “from the bench to the bedside”, and create
adequate infrastructure for progress from preclinical research to
phase-III trials.
Integration of databases. Support countries in creating
research databases for dementia therapeutics that are
harmonized internationally to streamline efforts and funding
for the development of dementia therapeutics, promote
collaboration and avoid unnecessary duplication. Databases
should include efforts by private industry and not-for-profit
actors.
International platforms. Building on national databases,
promote the establishment of an international drug
development platform to connect expertise in medicinal
chemistry, pharmacokinetics, toxicology, animal models and
trial design in order to fill any gaps in particular regions or
countries, thereby encouraging true collaboration while taking
into consideration sharing of intellectual property.
Milestone 8.1: By 2027, to have established
therapeutics development networks and national
research databases for dementia treatment, with
support from governments, academia, industry and
philanthropic organizations, and to have integrated
national databases into international platforms.
Milestone 8.2: By 2027, to have ensured that new trials
on treatment of diseases such as diabetes mellitus,
hypertension, stroke and coronary artery disease
include cognitive assessment as a secondary outcome
and make the data available to researchers for analysis
and consideration for repurposing of therapies.
Milestone 8.3: By 2030, to have developed diseasemodifying therapy for AD that is safe and affordable
and has a clear clinical benefit.
STRATEGIC GOAL 9
Improving clinical trials
Facilitate the translation of preclinical findings into human trials in all phases up to approval and
introduction of treatments, with hallmarks of the trials being efficiency, consistency and equity.
Actions:
Adaptive, efficient trial designs. Design more adaptive trials
of two or more treatments for use in combination.
Recruitment of patients and timing of interventions. As
the pathological processes that cause dementia often predate
the onset of clinical symptoms by many years, design trials
to recruit patients as early as possible when relevant to the
therapeutic strategy.
Harmonized international outcome measures. Improve
international collaboration for identifying and validating
outcome measures for clinical trials, including cognitive and
functional outcomes and biomarkers. Global consensus should
be sought on the acceptable safety of drugs, with consumer
involvement.
International guidance for trials: Based on the three actions
above, develop expert guidance on the design of clinical trials
for drug development to ensure global harmonization, equity
and safety to all.
International trial infrastructure. To ensure equity and
develop infrastructure for trials in both HIC and LMIC, so
that trials are international, gender-balanced, include all
populations, are fully transparent and provide equal access to
the data and results by researchers in all settings. A national
registry and a database of people who are interested in trial
participation should be established, and the research workforce
should be trained to ensure that they have the required skills
and competence. Triallists should ensure that trial participants
are appropriately supported after conclusion of the trials.
Milestone 9.1: By 2027, to have developed standardized
expert guidance on the design of clinical trials for drug
development.
Milestone 9.2: By 2027, to have developed capacity
in countries to conduct clinical intervention trials
for dementia, especially in LMIC, including basic
infrastructure and workforce and ensuring appropriate
involvement and recruitment of people living with
dementia.
Partnerships and collaboration for trials. Foster collaboration
among triallists, including researchers, clinicians, pharmacologists
and statisticians, and involve academia, clinical medicine,
industry and consumer organizations to agree on the designs and
outcome measures of efficient, adaptive trials.
6. Drug development and clinical trials for dementia
37
STRATEGIC GOAL 10
Legislative and regulatory environments
Develop legislative frameworks and appropriate regulatory environments in countries for the execution
of trials, approval of drugs and devices, cost–benefit analyses and post-marketing surveillance.
Actions:
National ethical and regulatory frameworks. Strengthen
national ethical and regulatory frameworks for clinical trials to
ensure international consistency, and reduce legal, regulatory
and administrative obstacles when possible. Efforts should be
made to harmonize such frameworks globally to avoid obstacles
to international collaboration.
Treatment development frameworks. Develop regulatory
frameworks for trials of new treatments, their approval for
clinical use and their post-approval surveillance, in line with
international standards.
38
A blueprint for dementia research
Health economics frameworks. Develop health economics
frameworks to evaluate the cost–benefit of a new treatment
before its approval, to be repeated subsequently as required in
the context of national health budgets and health priorities.
Guidance on approval requirements for new drugs.
Develop clear guidance for drug developers, highlighting the
requirements and milestones that need to be achieved for
approval.
Milestone 10.1: By 2027, countries to have
strengthened their national ethical and regulatory
frameworks for the conduct of trials, approval of
drugs and devices, their cost–benefit analysis and
post-marketing surveillance, that are internationally
harmonized.
© Chinnapong
7. Dementia care and
support
7.1 Context
Dementia requires complex care, and research
into dementia care must be based on both sound
evidence from health systems and robust clinical
and interventional science. Both aspects of dementia
care research are covered in this chapter, with
cross-links to relevant topics such as economics and
pathophysiology that are covered in other chapters.
Dementia services and support range from diagnosis
and treatment to secondary prevention of cognitive
and non-cognitive symptoms of dementia to longterm care, rehabilitation, end-of-life support and
services for carers and families (4). Ideally, these
services are provided in the community or in primary
care to allow people with dementia to live at home
as long as possible and continue to be part of their
communities. Coordinated home care models (87) and,
when necessary, person-centred institutional care
models (88) have been shown to be effective. There is,
however, increasing recognition that health and social
care systems worldwide are unable to meet these
complex needs (89, 90), and most low- and some middleincome countries have limited dementia or longterm care services (1, 57, 91). Even in HIC, the quality
of dementia care in the community and institutional
long-term care settings varies, and the services
often do not meet the needs of people with dementia
(92, 93). Globally, dementia care pathways are often
fragmented, are not person-centred (94) and often do
not reflect the research evidence.
Access to a well-trained dementia workforce also varies
by country. For instance, in almost one in five LMIC,
basic training in dementia is not provided to relevant
health-care cadres (e.g., doctors, nurses, nurse aids,
pharmaceutical personnel, social workers); such a lack
is seen in only 1 in 10 HIC (1, 57). Similarly, specialists with
expertise in diagnosing and treating dementia, such as
neurologists, geriatricians and psychogeriatricians, are
more common in HIC than LMIC, with median numbers
of psychogeriatricians per 100 000 population of 2.2
and 0.02, respectively (1). Insufficient numbers and an
40
under-skilled workforce are barriers to the provision of
good-quality dementia care (95, 96).
Important pillars of dementia care provision are family
members and close friends, who provide most of the
care for people with dementia, particularly in LMIC.
The bulk of the burden is borne by women: wives,
daughters and daughters-in-law (1). While there are
positive aspects to caregiving, it can negatively affect
the physical and mental health of carers. General lack
of knowledge on how to provide care for people living
with dementia also negatively impacts the prognosis.
Family carers should be given information, education,
support and access to formal care (97). Carer education
and support programmes have been shown to be
effective as well as cost–effective (98, 99).
While the world is searching for a cure or diseasemodifying treatments (see chapter 6), research
on dementia care has shifted from a predominant
focus on improving or maintaining cognition or
decreasing behavioural changes to outcomes
such as a better quality of life, positive living with
dementia, “reablement”, compensation for disability
and improving daily function, mood, social health,
community participation and social and emotional
communication.
Non-cognitive symptoms of dementia such as changes
in behaviour, often referred to as behaviours and
psychological symptoms associated with dementia,
are common, distressing and require additional
care (20). Growing evidence suggests that nonpharmacological interventions, such as psychosocial
interventions, are effective in preventing, reducing
or treating non-cognitive symptoms (100). Similarly,
evidence suggests that rehabilitative interventions
such as cognitive stimulation therapy, cognitive
rehabilitation, physical exercise and gait/balance
training can improve cognition, function, stability
and/or the quality of life of people with dementia
(101). Evidence is emerging that some psychosocial
interventions are effective when delivered remotely
on websites, apps and telehealth, and that assistive
products are valuable to promote and maintain optimal
levels of functioning and independence (102, 103).
7.2 Research gaps
Methodological issues in clinical
research
Harmonized methodologies and outcome
measures
For evaluating interventions, there is a lack of
appropriate methodologies and outcome measures
that reflect the priorities of people living with dementia
and their carers and that are suitable for different
cultural, language and regional contexts in both
formal and informal care settings. Approaches are also
required to measure and harmonize the outcomes of
interventions for under-researched aspects, including
social health, stigmatization and self-efficacy.
Non-pharmacological interventions
There is a lack of research on the cost–effectiveness
and acceptability of family-based psychosocial
support that harnesses the value systems of families
that are taking care of older family members, as for
other chronic mental and physical conditions (104).
Similarly, scalable, cost-effective interventions are
necessary to support carers of people living with
dementia, reduce the negative impact of caregiving
on carers’ health and improve the care of people with
dementia.
workers) could be involved in the identification and
safety of people with dementia who are lost and in
tracing their carers.
Delivery of care, the continuum of
care and health systems research
Models of care delivery and low-cost care
There is a lack of well-studied strategies for improving
dementia care throughout the care continuum, from
diagnosis to end-of-life care in primary or community
care, long-term care, hospitals and specialist settings.
Research on low-resource, low-cost but effective
models of care is essential, particularly for LMIC.
Implementation research
Insufficient implementation research is conducted to
understand barriers to care and to identify the best
ways to apply current evidence throughout the care
continuum, at all levels of health and social care systems.
Inequities in dementia care
Dementia care is often inequitable, especially for
people in rural areas, ethnic minorities, people with
disabilities, people living alone and other groups that
have poorer access to and quality of care (105). These
inequities are poorly described and accounted for, and
mitigating strategies are lacking to provide optimal
care for all.
Training and retention of the workforce
There is scarce evidence on how best to recruit, train
and then retain dementia specialists and generalists
and the long-term care workforce.
Psychosocial and biological basis of behaviours
and psychological symptoms associated with
dementia
Current interventions targeting behavioural changes
and psychological symptoms often focus only on
the manifesting symptoms and are not designed to
address their causes (see chapters 4 and 6).
Telehealth
Robust evidence is required on the cost–effectiveness
of telemedicine approaches and their adaptability
to ensure their acceptability and implementation.
Approaches to overcome low levels of technological
literacy and enabling of populations without Internet
access are also lacking.
Remote monitoring technologies
There is insufficient research into technologies that
combine sensors and smart home devices with
clinical monitoring. Such combination may allow
home monitoring and early intervention and thus
represent a potential means to reduce hospital
admissions, improve person-centred care and
promote independence. Evidence is also lacking on
how members of the community (e.g., police, transport
Health administrative data
Administrative data are not collected in many countries
and for subnational regions, or such systems are in
their early stages of development. More research is
necessary to reduce the barriers to collecting data.
Even in countries that do collect data, they have
often not been used in population-based research on
dementia care, especially in models of long-term care
suitable for low-resource settings.
7. Dementia care and support
41
7.3 Strategic goals, actions and milestones
STRATEGIC GOAL 11
Tools and methodologies for interventions
Have high-quality tools and methodologies for the design, adaptation and evaluation of dementia care
interventions that are applicable internationally and can be adapted locally.
Actions:
Collaboration in care interventions. Convene potential
collaborators (countries, philanthropic organizations, civil
society, private sector) and experts in evidence-based
interventions to study and implement care interventions
that target specific gaps in care provision, including support
and training of family carers in a sustainable manner and for
different settings and contexts.
Representative research designs. Design research that
includes person-centred, value-based outcome measures,
recruitment and data collection methods to ensure equitable
participation of underrepresented populations including
cultural and language adaptation for interventions. Conduct
research in environments as close to real-life settings as
possible, for example, in the home or in “living laboratories”.
Harmonized methods and frameworks. Develop and
disseminate health service research methods such as
interrupted time series, mixed methods case series, policy
reviews and health economics. Develop a harmonized
framework for contextualized, inclusive research design and
outcome measurement. Promote research on implementation
design and evaluation of interventions.
Interventions for the causes of behaviours and psychological
symptoms associated with dementia. Investigate how
to better incorporate the understanding of the biological,
psychosocial and environmental causes of behaviours and
psychological symptoms associated with dementia, into
42
A blueprint for dementia research
effective care interventions that target both its causes and
symptoms. These interventions should also be developed for
community settings outside institutional long-term care.
New technologies. Develop affordable, scalable, adaptable
technologies and collect high-quality data on the use
of innovative care solutions, including electronic health
records, medication trackers and reminders, sensors for
dementia-related measures (e.g., urinary tract infection, sleep
disturbances, behaviour change), fall and motion sensors and
personal emergency systems. This will require multidisciplinary
collaboration among experts in disciplines such as engineering,
data science and clinical medicine and people living with
dementia and carers.
Administrative data. Support research based on health
administration data, and support strengthening of such
systems in LMIC.
Milestone 11.1: By 2027, to have created a toolkit for
implementation of care interventions that can be
tailored to various areas of care provision and easily
adapted in different resource settings.
Milestone 11.2: By 2027, to have developed
internationally applicable guidance on the ethics,
practicality, capture, storage and use of health
administrative data on dementia.
STRATEGIC GOAL 12
Models across the continuum of care
Develop affordable and cost-effective care models across the continuum of care from diagnosis to the
end of life for primary care/community, long-term care, rehabilitation, hospital and specialist settings
that are appropriate for ethnic, regional, economic and cultural contexts.
Actions:
Culturally appropriate models. Invest in research into models
for delivery of high-quality care that is accessible in low-income
settings and to non-specialist personnel, including community
interventions for people living with dementia and their carers.
Promote research on the integration of different care models.
Specialist care models. Conduct research to evaluate specialist
care models of care for people with severe dementia and/or
severe behaviours and psychological symptoms associated with
dementia throughout the health and social care systems.
Telemedicine models. Research and develop new telemedicine
models that are easy to implement and adaptable to local
contexts, accounting for populations with restricted internet
access and low technological literacy.
Implementation in diverse contexts. Undertake research on
how models of care can be adapted to different cultures and
contexts, in particular in LMIC.
Barriers to access to care. Conduct research to improve
understanding of the barriers to access to care, particularly
in LMIC and marginalized communities, and identify health
system gaps, synergies and opportunities.
Workforce capacity. Promote research to understand the
training requirements for the dementia care workforce,
particularly in LMIC, and how they can be met with effective,
affordable, sustainable education and training. Research should
also be conducted to determine how the workforce can be
recruited and retained in the numbers required.
Milestone 12.1: By 2030, to have evidence-based,
effective, sustainable models of community and
institutional long-term care and rehabilitation
programmes that are tailored to populations, culturally
appropriate, financially viable, account for diversity in
the population and prioritize the needs of people with
dementia and their carers.
7. Dementia care and support
43
© serts
8. Dementia risk reduction
8.1 Context
Twelve potentially modifiable risk factors across the
lifespan account for up to 40% of dementia cases
worldwide (106) (Fig. 5). As many of the risk factors for
dementia are also those for NCDs, effective integration
of dementia risk reduction into programmes such as for
tobacco cessation, cardiovascular disease prevention
and nutrition is an important public health strategy.
The WHO Guidelines on risk reduction of cognitive
decline and dementia (107) provide support for countries
in designing public health interventions to reduce the
risks of cognitive decline and dementia (Fig. 5).
Apart from the risk factors already identified, others
are being investigated and may emerge as important
targets for reducing the risk of dementia, such as
use of certain medications, insufficient sleep and
infections. Risk and protective factors also differ by
ethnic group and geographical location, and their
prevalence is changing in most regions. As average
educational attainment increases and other modifiable
risk factors are better addressed in some countries,
inequalities during the life course, such as in access to
care, treatments and healthy diets, may become more
marked and create barriers to preventive measures.
Fig. 5. Modifiable risk factors for dementia and recommendations for interventions to reduce risk from WHO
guidelines
Evidence-based risk factors
from the Lancet commission on
dementia prevention, intervention
and care (2020):












less education
hypertension
hearing impairment
smoking
obesity
depression
physical inactivity
diabetes
low social contact
excessive alcohol consumption
traumatic brain injury
air pollution.
Evidence-based recommendations
for interventions to reduce the
risk of dementia from WHO
guidelines (2019):









physical activity interventions
tobacco cessation interventions
nutritional interventions
interventions for alcohol use disorders
cognitive interventions
weight management
management of hypertension
management of diabetes mellitus
management of dyslipidaemia.
More evidence required for:
• management of depression
• management of hearing loss
• interventions to increase social activity.
Sources: Dementia prevention, intervention, and care: 2020 report of the Lancet Commission (106) and Risk reduction of cognitive decline and dementia: WHO guidelines
(107).
45
While many risk factors are the same as those for other
NCDs, such as cardiovascular disease and diabetes,
some are specific to dementia and are attracting more
research. For example, social health (108), which includes
consideration of a person’s social context (such as
living situation, relationship status, social network size),
its function (such as social support) and its quality
(such as satisfaction with relationships, loneliness)
(109). The association between poor social health (i.e.,
a small social network, infrequent social interactions,
little social support) and the risk of cognitive decline or
incident dementia is now well established (106, 110–112).
Furthermore, the risk of cognitive impairment or
dementia has been linked to the built environment,
which comprises the physical environment in which
people live, work, travel and socialize (113). Research
suggests an association between exposure to
neighbourhood resources such as green spaces and
positive cognitive outcomes (114) while an increased risk
of dementia is observed with exposure to air pollution
and pesticides (115, 116).
In view of projected worldwide demographic ageing and
the lack of a cure or widely accepted disease-modifying
treatment for dementia, it is important to reduce the
individual and population risks of dementia. Evidence
suggests that modification of lifestyle and other risk
factors can slow cognitive decline and delay the onset
of dementia or prevent it altogether (117).
People are exposed to dementia risk factors throughout
their lives, with the basis of brain health established in
utero (17). Maternal malnutrition, prenatal exposures
to toxins and perinatal morbidity directly affect brain
health. Childhood malnutrition, less education and
adverse childhood experiences also impact brain
health in early life, while other risk factors, including
comorbid conditions and social adversity affect brain
health in mid- and later life (17). Many of these risk
factors (e.g., air pollution) are beyond the control of
individuals or even a subset of the population (e.g.,
being unable to afford healthy diets or living in areas
that are unsafe for outdoor exercise). Work on dementia
prevention has comprised mainly individual behaviour
change rather than approaches for whole populations
(118). Observational studies supplemented by a small
but growing number of controlled trials now make
a persuasive case for action to reduce the risk of
dementia at both policy and population levels and for
individual-level interventions (106).
46
A blueprint for dementia research
While treating individual risk factors is important,
the evidence is strongest for lifelong accumulation
of multiple risk factors for dementia (119). Primordial
prevention programmes can have strong positive
effects on society by establishing conditions and
opportunities for healthy communities and healthy
lifestyles before birth and throughout the life course.
Therefore, multimodal individual and population
interventions targeting several risk factors concurrently
over time have been proposed and used. The best
known is the Finnish Geriatric Intervention Study to
Prevent Cognitive Impairment and Disability (FINGER
trial) (120), which showed a 25% greater improvement
in global cognition in the intervention group than in
the control group that received only general health
advice. Building on these promising findings, the Worldwide FINGERS network involves research teams in
over 40 countries and is an example of adaptation of
a multidomain intervention for diverse geographical
and cultural settings (121). While there is some evidence
that multidomain interventions have benefits in terms
of cognitive decline, they have not yet been shown
to be effective in reducing incident dementia or mild
cognitive impairment (119).
8.2 Research gaps
Methodology
Strength and representativeness of evidence
The strength of evidence differs for different modifiable
risk factors and interventions for reducing the risk
of dementia (106, 107). Some interventions to modify
certain risk factors such as use of hearing aids and
antidepressant medications and interventions for
increasing social activity require more robust, highquality evidence. Little evidence is available on
modifiable risk factors in LMIC or in culturally, sexually
and linguistically diverse sub-populations in both HIC
and LMIC (106, 122).
Methodology for interventions
Given the many risk factors associated with dementia,
approaches to reduce risks are likely to be more
effective in combination. There is currently a lack
of robust methodologies for evaluating the impact
and efficacy of combined individual and population
approaches.
Harmonization of measures
Inconsistencies in conceptual definitions, methodologies
and measures of risk factors and outcomes limit the
ability to compare data from different sources (123).
More precise measures of interindividual variation and
longitudinal change are also lacking (124, 125).
Lifespan approach
Most of the evidence on risk factors and interventions
is for cohorts of older adults (125) exposed in mid-life
(106), with limited long-term data (107, 124). There is a
lack of evidence on exposure throughout the lifespan,
from prenatal to early and mid-life, on mitigation of
risk factors and on the use and effectiveness of such
interventions for people aged ≥ 85 years (a rapidly
growing segment of the population) and for people
already living with dementia.
Risk factors and interventions
Biological mechanisms
The biological mechanisms underpinning the relation
between modifiable risk factors and brain health are
poorly understood (124). There are also few robust data
on sex-specific risk factors such as early menopause
and complications during pregnancy and on the
differential effect of risk factors in men and women, as
recently shown for cardiovascular events (125).
Social health
Social connections, comprising social structure,
function and quality, has often been addressed only
partly in cohort studies, from single-item measures
instead of validated scales (111). Furthermore, they often
address social connections in late life rather than in
mid-life, and data on social connections in LMIC (127)
and from culturally, linguistically and gender-diverse
subpopulations are lacking. There are no measures
of social adaptation in the face of chronic illness.
More theoretical and psychometric work is needed to
extend knowledge of social health as a risk factor for
dementia. Moreover, few prospective studies have been
conducted, which would reduce potential bias due to
reverse causality (i.e., cognitive decline causing poor
social health).
Contemporary cohorts
More data are required on modifiable risk factors
in contemporary cohorts (124) in view of the global
changes in risk factors, such as greater longevity
and an increased prevalence of vascular risk factors
(diabetes, hypertension, obesity) in some LMIC (122).
Participants from some birth cohort studies, such as
the British 1946 cohort (128), have now reached old age
and would be highly relevant for modelling life course
exposure to risk and late-life outcomes.
Risk scores
Several risk scores have been developed, some of which
have been validated and used in tools for widespread
screening (129). For accurate prediction of the risk of
dementia, risk scores include both modifiable and nonmodifiable risk factors, such as age and sex. No risk
scores have been developed specifically for LMIC, and
only a few tools developed in HIC have been found to
be suitable for use in LMIC (118).
Interactive effects
There is little evidence on the potentially interactive
effects of modifiable risk factors, which has implications
for the optimal design of multidomain interventions,
their cost–effectiveness and the identification of best
buys.
Whole-population approaches to dementia risk
reduction
More evidence is necessary for the implementation
of whole-population approaches, which require
commitment from diverse stakeholders, including
government, industry and workplaces. These include
investment in green spaces and built infrastructure to
promote physical activity, policies to promote access
to healthy diets and decrease the salt content in food,
age-friendly environments, internet access in rural
areas to improve social cohesion and integration and
policies for decreasing air pollution (17, 118).
Outcome measures
Few intervention studies on dementia risk reduction
have included incident dementia as the outcome (107) or
classified the incidence of dementia (124). Dementia risk
scores may be useful surrogate outcomes in prevention
trials, but evidence for their validity is currently limited.
Implementation
There has been little research on implementation
strategies, particularly in LMIC, and on the effectiveness
of individual behaviour change outside the controlled
environment of a clinical trial (118). Promising
interventions must be appropriately tailored for diverse
contexts before their effectiveness can be assessed
and their scalability and sustainability adequately
accounted for to maximize benefits.
8. Dementia risk reduction
47
8.3 Strategic goals, actions and milestones
STRATEGIC GOAL 13
Methodologies and approaches for risk reduction research
Improve and generate standardized methodology for research on risk reduction, reach consensus
on outcome measures, improve the diversity of samples, and promote collaboration and consumer
participation.
Actions:
Develop a framework for global harmonization of data.
Develop international guidelines to harmonize standards and
best practice, building on projects such as World-Wide FINGERS
(121). International consensus should be reached on measures
of risk factors and outcomes, increasing synergy with preventive
measures for other NCDs and with appropriate diversity and
representation.
Adopt a life course perspective, including early life
experience. Start new birth cohorts and maintain existing ones
(and/or extend their outcome measures to include cognitive
and neuroimaging variables) to obtain prospective lifelong
epidemiological data. Individuals who develop dementia
during follow-up periods should remain in cohorts and not
be excluded. Consider age and cumulation of exposure to risk
factors in retrospective cohorts.
Develop methods to assess interventions at various levels.
Support the development of methods to evaluate and generate
high-quality data on large-scale, multi-domain interventions
with individual, whole-population and a combination of both
approaches to risk reduction.
Increase diversity and representativeness. As risk factors
can vary among population groups, prioritize diversity and
representativeness (especially with respect to LMIC, culturally
and linguistically diverse subpopulations, Indigenous peoples
and other marginalized communities). Funders should require
applicants to address this aspect by designing research in
collaboration with diverse stakeholders.
48
A blueprint for dementia research
Include incident dementia and cognition as outcome
measures. Ensure that population-level and policy research
on other diseases include cognition and dementia incidence
(including disease subtypes) as outcome measures. Treatment
trials for NCDs that are risk factors for dementia (including
diabetes mellitus, hypertension, coronary artery disease,
stroke) must include cognitive assessment and/or neuroimaging
in order to explore the role of treatment on cognitive outcomes.
Facilitate data collection in many fields (e.g., health,
education, environment). Promote capacity-building in data
science and “big data” to ensure optimal, ethical use of large
datasets from various sectors (e.g., national, administrative
and online data, medical records) and linkage to observational
and interventional datasets. Projects such as the Methods for
longitudinal studies in dementia (130), the DEMON Network
(131), the Social Health and Reserve in the Dementia Patient
Journey project (132) and the iMAP cohort study (133) for the
built environment should be expanded. Data-sharing and
harmonization are also applicable to strategic goals 14 and 15.
Milestone 13.1: By 2027, to have reached international
consensus on outcome measures for studies of risk
factors and prevention that are flexible enough to
include new risk factors and methodological advances
in the measurement of risk factors.
Milestone 13.2: By 2027, to have a framework for
harmonization of data on risk reduction.
STRATEGIC GOAL 14
Understanding risk factors
Develop a better understanding of the risk factors for dementia, including the diverse health, social
and environmental determinants of brain health, resilience and promotion mechanisms, as well as
differences between and within countries.
Actions:
Dementia risk factors within the context of brain health
promotion. Foster research on the effects of wider brain
health determinants across the life course on dementia risk at
individual and population level (17).
– Promote research to improve the quality of evidence and
investigate physical health determinants of dementia and
brain health more broadly, including maternal health,
genetic and epigenetic factors, nutrition, infections,
comorbidity with other NCDs and sensory impairment,
traumatic brain injuries and health behaviours.
– Examine the extent to which the level of education
influences the rate of dementia. Investigate whether
protective factors reduce the incidence of dementia by
improving cognitive reserve (e.g., social interaction,
multilingualism, complexity of occupation, physical activity
and other indicators of a healthy lifestyle).
– Promote research to better understand the impact of air
pollution and climate change, health emergencies such as
the COVID-19 pandemic and exposure to chemicals (e.g.,
heavy metals and pesticides) on the brain and dementia risk.
Inequality and cultural differences. Investigate how social,
financial and health inequalities and various cultural aspects
impact the determinants listed above. Conduct longitudinal
studies to better understand the impact of structural, economic
and social inequalities on the risk of developing dementia and
how interventions aiming to mitigate these inequalities can be
designed, implemented at scale, and yield positive outcomes.
Risk scores. Develop scores for modifiable and non-modifiable
risk factors that can be used in various resource environments
and regions and that take into account the entire life course.
Milestone 14.1: By 2027, to have initiated
comprehensive analytical epidemiological studies in
diverse ethnic, regional and geographical settings to
address current inequity in data availability and to
understand changes in the prevalence and incidence of
risk factors.
Milestone 14.2: By 2027, to have established and
validated risk scores for identification of individuals
who are likely to develop dementia.
Interactive risk factors. Given the multifactorial etiology
of dementia and the interactive effects of modifiable and
non-modifiable risk factors on dementia risk, use multidomain
approaches to study reduction of dementia risk.
8. Dementia risk reduction
49
STRATEGIC GOAL 15
Risk reduction interventions
Generate robust evidence of the efficacy, cost-effectiveness and return on investment of interventions
to reduce the risk of dementia across the life course and in different settings. This should include
promotion of healthy behaviours and non-pharmacological interventions for both individual behaviour
change and societal approaches, grounded in better awareness and understanding of dementia by the
general population, to promote informed, extensive adherence to risk reduction programmes.
Actions:
Evidence of interventions. In line with the 2019 WHO
Guidelines on reducing the risk of cognitive decline and
dementia (107), the following actions should be taken according
to the strength of current evidence:
– High-quality evidence. For these interventions (e.g., for
management of hypertension), conduct and evaluate
the outcomes of large individual and population-based
interventions, including post-implementation surveillance
and policy analysis; and study approaches to improve the
scalability and generate evidence on return of investment.
– Moderate-quality evidence. For these interventions (e.g.,
for physical activity), conduct large randomized controlled
trials of single or multiple domains, and use evidence for
policy making and implementation at population level.
– Low-quality evidence. For these interventions (e.g., for
cognitive interventions), perform large-scale clinical trials
with appropriate representation of minority populations and
standardized methods to develop strategies for improving
the robustness and reliability of data.
– Insufficient evidence. For these interventions (e.g., for
management of depression), facilitate the conduct of
high-quality clinical trials on safety and efficacy and on
implementation strategies to reduce the risk of cognitive
decline and/or dementia.
Population approaches. Derive robust, representative data
on the effectiveness of population or policy interventions,
such as taxation of alcohol, tobacco and sugar, prevention
of head injuries and reducing air pollution and the use of
pesticides. The scale and intensity of these interventions must
be proportionate and tailored to the degree of disadvantage in
an entire community and in subpopulations of that community
(118).
WHO risk reduction guidelines. Update the WHO Guidelines on
risk reduction of cognitive decline and dementia with the new
evidence generated.
50
A blueprint for dementia research
Interventions at various levels. Initiate studies to understand
the efficacy of both individual and population-level
interventions for risk reduction, and investigate potential
synergistic effects.
Interventions across the life course. Initiate ambitious,
large-scale, long-term studies starting early in life, or extend
existing studies to investigate incident dementia or cognition as
outcomes; also, validate other measures as surrogate or proxy
end-points for diverse populations. The risk scores described
in strategic goal 14 are promising surrogate end-points, but
their validity should be established across the life course and in
different national and sub-national contexts (134).
Novel technologies. In the context of both single and multidomain interventions to enhance cognition and brain health,
assess the efficacy of and adherence to new technologies and
e-health solutions to scale up and broaden the reach of risk
reduction interventions, including in LMIC and under-resourced
subpopulations in HIC. The extent to which these solutions are
effective in isolation or require additional face-to-face support
should also be considered.
Milestone 15.1: By 2027, to have extended the breadth
and geographical representativeness of studies
of individual- and population-level approaches to
dementia risk reduction, including not only individual
behaviour changes but also the efficacy of policy
interventions.
Milestone 15.2: By 2030, to have established evidence
of efficient interventions on health, environmental and
social determinants that reduce the risk for dementia
throughout the life course.
© Image-Source
9. Conclusion
The blueprint for dementia research is WHO’s first
initiative of this kind in the context of non-infectious
diseases. It acknowledges that significant scientific
advances have been made in the last decades towards
a better understanding of dementia and its underlying
diseases. Yet, collectively, we are far behind finding
a cure for dementia by 2025, a goal set during the
2013 G8 dementia summit, or achieving the global
targets outlined in the global action plan on the public
health response to dementia 2017—2025. Addressing
this challenge requires the global prioritisation of
dementia, and this blueprint will support coordinating
efforts among stakeholders, closing research gaps,
fast-tracking research development and innovation,
as well as ensuring the successful implementation of
research outcomes.
WHO’s blueprint for dementia research summarizes
the current state of dementia research across six
broad research themes, identifies existing research
gaps, and outlines 15 strategic goals with actions
and timebound milestones to address these gaps.
For example, the blueprint reiterates our still limited
understanding of the underlying diseases causing
dementia and the dire need for disease-modifying
therapies, better diagnostic tools, and care strategies.
The blueprint also emphasizes the urgency to
strengthen evidence on risk factors and effective
risk reduction interventions, as well as to develop
better methodologies to track epidemiological trends,
identify cost-effective interventions, and measure the
economic impact associated with dementia.
To accelerate global research efforts related to dementia
and to create an enabling research environment,
the blueprint identifies eight cross-cutting drivers of
research. For instance, an essential driver of research
is the empowerment and engagement of people with
lived experience in all aspects of research including, but
certainly not limited to, training and capacity building of
researchers; their engagement in research will increase
the impact of scientific discoveries and ensure that
research meets the needs of people most affected by
dementia. Other drivers essential to the advancement
of dementia research include diversity and equity;
funding; access to science, data and materials;
capacity building for research; technology; knowledge
translation; and regulatory environments. To bring
52
about impactful scientific advances for dementia, it is
imperative to implement and monitor these drivers so
that they become the norm rather than rare examples
of good practice.
As the global research community and political
decision-makers learn from the COVID-19 pandemic
response, stakeholders at all levels — including
people with lived experience, researchers, funders,
and policy makers — must collaborate and set out
comprehensive strategies for the adequate and timely
response to dementia. As such, WHO encourages
national and international research agencies, together
with other funding bodies, to use this blueprint to
inform upcoming funding streams and operationalize
the outlined drivers of research. Civil society can
ensure that advocacy efforts are likewise aligned,
supporting the drive for a more equitable, efficient, and
collaborative research landscape. Finally, researchers
can support the achievement of milestones and
strategic goals of this blueprint by addressing the
research gaps identified.
The implementation, impact, and achievement of the
milestones detailed in this blueprint will be measured
using existing WHO frameworks and resources, such
as the Global Dementia Observatory, WHO Global
Health Observatory, WHO Global Observatory on Health
Research and Development, WHO’s Health Equity
Monitor. In addition, WHO’s monitoring mechanisms for
the blueprint are aligned with the Global action plan
on the public health response to dementia 2017–2025,
the Intersectoral global action plan on epilepsy and
other neurological disorders 2022–2031, as well as
with SDGs targets and other World Health Assembly
mandates. Other existing monitoring platforms and
information gathered from academic literature and
reports will also be included. In addition, to support
monitoring efforts, regular technical meetings and
seminars will be held with relevant stakeholders,
which will inform on the scientific progress.
WHO will work with all stakeholders across relevant
sectors to ensure that the actions outlined in the
blueprint are implemented, milestones are achieved,
and strategic goals are realised, with the ultimate goal
of improving the quality of life of and supports offered
to people living with dementia, their carers and families.
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Annex
Summary of research themes, strategic
goals and milestones
Research theme
Dementia
epidemiology
and
economics
Strategic goals
Milestones
Strategic goal 1: Ensure availability of
high-quality epidemiological data from
widely representative geographical,
ethnic and socioeconomic groups with
appropriate disaggregation by gender
and sex, age, disease severity and
subtypes and relevant measures of
inequity.
Milestone 1.1: By 2027, to have international benchmarks for
epidemiological studies and use of open-access, inter-operable,
international platforms to archive and share epidemiological data from
regions around the world.
Milestone 1.2: By 2030, to have a comprehensive dataset from highquality epidemiological studies that include geographical, ethnic and
regional populations for whom there are currently insufficient data to fill
major gaps in international data.
Milestone 1.3: By 2030, to have ensured that countries have highquality dementia registries to monitor dementia and the quality of its
assessment and care.
Strategic goal 2: Establish better
understanding of the economic impact of
dementia on society, and generate robust
evidence on the cost–effectiveness of risk
reduction, treatment and care.
Milestone 2.1: By 2027, to have established a database on burden of
disease and cost estimates for dementia from different geographical,
ethnic and regional groupings around the world.
Milestone 2.2: By 2030, to have generated robust evidence on the
cost–effectiveness of treatment and care interventions and strategies
to reduce the risk of dementia to support establishment of public health
interventions throughout the life course.
Strategic goal 3: Increase
understanding of the origins and
mechanisms of the diseases that cause
dementia through a life course approach.
Milestone 3.1: By 2027, to have developed an international collaborative
network for sharing basic scientific data and techniques, technical
innovations and materials that includes both HIC and LMIC, academia,
government and industry.
Milestone 3.2: By 2027, to have established new life course cohorts to
investigate the development and progression of various diseases causing
dementia.
Milestone 3.3: By 2030, to increase understanding of the cellular
and molecular mechanisms (e.g., protein aggregation, inflammation,
lysosomal dysfunction, oxidative stress) of the different diseases causing
dementia and the relevance of determinants and pathways throughout
the life course.
Strategic Goal 4: Develop models of
the diseases that cause dementia that
reflect their complex mechanisms and
downstream molecular events.
Milestone 4.1: By 2030, to have improved ex-vivo and animal models
that represent molecular disease characteristics and phenotypes, and are
ecologically valid for dementia in humans and underlying diseases.
Dementia
disease
mechanisms
and models
59
Annex: Summary of research themes, strategic goals and milestones continued
Research theme
Diagnosis of
dementia
Strategic goals
Milestones
Strategic goal 5: Develop highly
sensitive, specific diagnostic for
neurodegenerative disease that are
cost-effective and can distinguish the
underlying diseases that cause dementia.
Milestone 5.1: By 2027, to have developed an affordable test for
diagnosis of AD that is acceptable worldwide.
Milestone 5.2: By 2030, to have developed affordable tests for diagnosis
of non-AD dementias such as dementia with Lewy bodies, frontotemporal
dementia and neurogenerative diseases associated with TDP-43.
Strategic goal 6: Develop or improve
clinical assessments of cognition and
function that are applicable to diverse
settings and cover the entire disease
spectrum.
Milestone 6.1: By 2027, to have developed and incorporated into
existing digital platforms curated clinical assessment tools for dementia
diagnosis that are open access, used in primary care, culturally fair and
readily adaptable to different contexts.
Strategic goal 7: Improve
understanding and diagnosis of
prodromal stages of diseases causing
dementia and of the clinical, legislative
and economic implications of such
diagnosis.
Milestone 7.1: By 2030, to have developed diagnostic benchmarks for
diseases causing dementia at the prodromal stages (such as mild cognitive
decline and subjective cognitive decline) that are applicable in diverse
settings and are identified by accessible markers.
Strategic goal 8: Develop novel
molecules, repurpose drugs currently in
use or newly developed and investigate
next-generation biotherapeutics for
effective treatment of dementia.
Milestone 8.1: By 2027, to have established therapeutics development
networks and national research databases for dementia treatment,
with support from governments, academia, industry and philanthropic
organizations, and to have integrated national databases into
international platforms.
Milestone 8.2: By 2027, to have ensured that new trials on treatment
of diseases such as diabetes mellitus, hypertension, stroke and coronary
artery disease include cognitive assessment as a secondary outcome and
make the data available to researchers for analysis and consideration for
repurposing of therapies.
Milestone 8.3: By 2030, to have developed disease-modifying therapy
for AD that is safe and affordable and has a clear clinical benefit.
Strategic goal 9: Facilitate the
translation of preclinical findings
into human trials in all phases up to
approval and introduction of treatments,
hallmarks of the trials being efficiency,
consistency and equity.
Milestone 9.1: By 2027, to have developed standardized expert guidance
on the design of clinical trials for drug development.
Milestone 9.2: By 2027, to have developed capacity in countries to
conduct clinical intervention trials for dementia, especially in LMIC,
including basic infrastructure and workforce and ensuring appropriate
involvement and recruitment of people living with dementia.
Strategic goal 10: Develop legislative
frameworks and appropriate regulatory
environments in countries for the
execution of trials, approval of drugs and
devices, cost–benefit analyses and postmarketing surveillance.
Milestone 10.1: By 2027, countries to have strengthened their national
ethical and regulatory frameworks for the conduct of trials, approval
of drugs and devices, their cost–benefit analysis and post-marketing
surveillance, that are internationally harmonized.
Drug
development
and clinical
trials for
dementia
60
A blueprint for dementia research
Annex: Summary of research themes, strategic goals and milestones continued
Research theme
Dementia care
and support
Dementia risk
reduction
Strategic goals
Milestones
Strategic goal 11: Have high-quality
tools and methodologies for the design,
adaptation and evaluation of dementia
care interventions that are applicable
internationally and can be adapted
locally.
Milestone 11.1: By 2027, to have created a toolkit for implementation
of care interventions that can be tailored to various areas of care provision
and easily adapted in different resource settings.
Milestone 11.2: By 2027, to have developed internationally applicable
guidance on the ethics, practicality, capture, storage and use of health
administrative data on dementia.
Strategic goal 12: Develop affordable
and cost-effective care models across the
continuum of care from diagnosis to the
end of life for primary care/community,
long-term care, rehabilitation,
hospital and specialist settings that
are appropriate for ethnic, regional,
economic and cultural contexts.
Milestone 12.1: By 2030, to have evidence-based, effective, sustainable
models of community and institutional long-term care and rehabilitation
programmes that are tailored to populations, culturally appropriate,
financially viable, account for diversity in the population and prioritize the
needs of people with dementia and their carers.
Strategic goal 13: Improve and
generate standardized methodology
for population-based research on risk
reduction, reach consensus on outcome
measures, improve the diversity of
samples, and promote collaboration and
consumer participation.
Milestone 13.1: By 2027, to have reached international consensus on
outcome measures for studies of risk factors and prevention that are
flexible enough to include new risk factors and methodological advances
in the measurement of risk factors.
Milestone 13.2: By 2027, to have a framework for harmonization of data
on risk reduction.
Strategic goal 14: Develop a better
understanding of the risk factors for
dementia, including the diverse health,
social and environmental determinants
of brain health, resilience and promotion
mechanisms, as well as differences
between and within countries.
Milestone 14.1: By 2027, to have initiated comprehensive analytical
epidemiological studies in diverse ethnic, regional and geographical
settings to address current inequity in data availability and to understand
changes in the prevalence and incidence of risk factors.
Milestone 14.2: By 2027, to have established and validated risk scores
for identification of individuals who are likely to develop dementia.
Strategic goal 15: Generate robust
evidence of the efficacy, cost-effectiveness
and return on investment of interventions
to reduce the risk of dementia across the
life course and in different settings. This
should include promotion of healthy
behaviours and non-pharmacological
interventions for both individual behaviour
change and societal approaches, grounded
in better awareness and understanding
of dementia by the general population, to
promote informed, extensive adherence to
risk reduction programmes.
Milestone 15.1: By 2027, to have extended the breadth and
geographical representativeness of studies of individual- and populationlevel approaches to dementia risk reduction, including not only individual
behaviour changes but also the efficacy of policy interventions.
Milestone 15.2: By 2030, to have established evidence of efficient
interventions on health, environmental and social determinants that
reduce the risk for dementia throughout the life course.
Annex: Summary of research themes, strategic goals and milestones
61
Department of Mental Health and
Substance Use
World Health Organization
Avenue Appia 20
1211 Geneva
Switzerland
https://www.who.int/health-topics/
dementia